CNS Autoimmunity Research Articles

Analysis of CNS autoimmunity in genetically diverse mice reveals unique phenotypes and mechanisms.

Multiple sclerosis (MS) is a complex disease with significant heterogeneity in disease course and progression. Genetic studies have identified numerous loci associated with MS risk, but the genetic basis of disease progression remains elusive. To address this, we leveraged the Collaborative Cross (CC), a genetically diverse mouse strain panel, and experimental autoimmune encephalomyelitis (EAE). The thirty-two CC strains studied captured a wide spectrum of EAE severity, trajectory, and presentation, including severe-progressive, monophasic, relapsing remitting, and axial rotary (AR)-EAE, accompanied by distinct immunopathology. Sex differences in EAE severity were observed in six strains. Quantitative trait locus analysis revealed distinct genetic linkage patterns for different EAE phenotypes, including EAE severity and incidence of AR-EAE. Machine learning-based approaches prioritized candidate genes for loci underlying EAE severity (Abcc4 and Gpc6) and AR-EAE (Yap1 and Dync2h1). This work expands the EAE phenotypic repertoire and identifies novel loci controlling unique EAE phenotypes, supporting the hypothesis that heterogeneity in MS disease course is driven by genetic variation.

Patterns of cerebral damage in multiple sclerosis and aquaporin-4 antibody-positive neuromyelitis optica spectrum disorders-major differences revealed by non-conventional imaging.

Multiple sclerosis and aquaporin-4 antibody neuromyelitis optica spectrum disorders are distinct autoimmune CNS disorders with overlapping clinical features but differing pathology. Multiple sclerosis is primarily a demyelinating disease with the presence of widespread axonal damage, while neuromyelitis optica spectrum disorders is characterized by astrocyte injury with secondary demyelination. Diagnosis is typically based on lesion characteristics observed on standard MRI imaging and antibody testing but can be challenging in patients with in-between clinical presentations. Non-conventional MRI techniques can provide valuable diagnostic information by measuring disease processes at the microstructural level. We used non-conventional MRI to measure markers of axonal loss in specific white matter tracts in multiple sclerosis and neuromyelitis optica spectrum disorders, depending on their relationship with focal lesions. Patients with relapsing-remitting multiple sclerosis (n = 20), aquaporin-4 antibody-associated neuromyelitis optica spectrum disorders (n = 20) and healthy controls (n = 20) underwent a 3T brain MRI, including T1-, T2- and diffusion-weighted sequences, quantitative susceptibility mapping and phase-sensitive inversion recovery sequence. Tractometry was used to differentiate tract fibres traversing through white matter lesions from those that did not. Neurite density index was assessed using neurite orientation dispersion and density imaging model. Cortical damage was evaluated using T1 relaxation rates. Cortical lesions and paramagnetic rim lesions were identified using phase-sensitive inversion recovery and quantitative susceptibility mapping. In tracts traversing lesions, only one out of 50 tracts showed a decreased neurite density index in multiple sclerosis compared with neuromyelitis optica spectrum disorders. Among 50 tracts not traversing lesions, six showed reduced neurite density in multiple sclerosis (including three in the cerebellum and brainstem) compared to neuromyelitis optica spectrum disorders. In multiple sclerosis, reduced neurite density was found in the majority of fibres traversing (40/50) and not traversing (37/50) white matter lesions when compared to healthy controls. A negative correlation between neurite density in lesion-free fibres and cortical lesions, but not paramagnetic rim lesions, was observed in multiple sclerosis (39/50 tracts). In neuromyelitis optica spectrum disorders compared to healthy controls, decreased neurite density was observed in a subset of fibres traversing white matter lesions, but not in lesion-free fibres. In conclusion, we identified significant differences between multiple sclerosis and neuromyelitis optica spectrum disorders corresponding to their distinct pathologies. Specifically, in multiple sclerosis, neurite density reduction was widespread across fibres, regardless of their relationship to white matter lesions, while in neuromyelitis optica spectrum disorders, this reduction was limited to fibres passing through white matter lesions. Further studies are needed to evaluate the discriminatory potential of neurite density measures in white matter tracts for differentiating multiple sclerosis from neuromyelitis optica spectrum disorders.

Anti-Neuroinflammatory Effects of a Novel Bile Acid Derivative.

In the search for novel potent immunomodulatory nuclear factor-erythroid 2 related factor 2 (Nrf2) activators, a derivative of cholic bile acid, SB140, was synthesized. The synthesis of SB140 aimed to increase the electrophilic functionality of the compound, enhancing its ability to activate Nrf2. Effects of SB140 on microglial cells, myeloid-derived cells (MDC), and T cells were explored in the context of (central nervous system) CNS autoimmunity. SB140 potently activated Nrf2 signaling in MDC and microglia. It was efficient in reducing the ability of microglial cells to produce inflammatory nitric oxide, interleukin (IL)-6, and tumor necrosis factor (TNF). Also, SB140 reduced the proliferation of encephalitogenic T cells and the production of their effector cytokines: IL-17 and interferon (IFN)-γ. On the contrary, the effects of SB140 on anti-inflammatory IL-10 production in microglial and encephalitogenic T cells were limited or absent. These results show that SB140 is a potent Nrf2 activator, as well as an immunomodulatory compound. Thus, further research on the application of SB140 in the treatment of neuroinflammatory diseases is warranted. Animal models of multiple sclerosis and other inflammatory neurological disorders will be a suitable choice for such studies.

Dietary ellagic acid therapy for CNS autoimmunity: Targeting on Alloprevotella rava and propionate metabolism

BackgroundMediterranean diet rich in polyphenolic compounds holds great promise to prevent and alleviate multiple sclerosis (MS), a central nervous system autoimmune disease associated with gut microbiome dysbiosis. Health-promoting effects of natural polyphenols with low bioavailability could be attributed to gut microbiota reconstruction. However, its underlying mechanism of action remains elusive, resulting in rare therapies have proposed for polyphenol-targeted modulation of gut microbiota for the treatment of MS.ResultsWe found that oral ellagic acid (EA), a natural polyphenol rich in the Mediterranean diet, effectively halted the progression of experimental autoimmune encephalomyelitis (EAE), the animal model of MS, via regulating a microbiota-metabolites-immunity axis. EA remodeled the gut microbiome composition and particularly increased the relative abundances of short-chain fatty acids -producing bacteria like Alloprevotella. Propionate (C3) was most significantly up-regulated by EA, and integrative modeling revealed a strong negative correlation between Alloprevotella or C3 and the pathological symptoms of EAE. Gut microbiota depletion negated the alleviating effects of EA on EAE, whereas oral administration of Alloprevotella rava mimicked the beneficial effects of EA on EAE. Moreover, EA directly promoted Alloprevotella rava (DSM 22548) growth and C3 production in vitro. The cell-free supernatants of Alloprevotella rava co-culture with EA suppressed Th17 differentiation by modulating acetylation in cell models. C3 can alleviate EAE development, and the mechanism may be through inhibiting HDAC activity and up-regulating acetylation thereby reducing inflammatory cytokines secreted by pathogenic Th17 cells.ConclusionsOur study identifies EA as a novel and potentially effective prebiotic for improving MS and other autoimmune diseases via the microbiota-metabolites-immunity axis.7AEBLBqRMMqqUZLLsSi8h5Video

Deletion of voltage-gated calcium channels in astrocytes decreases neuroinflammation and demyelination in a murine model of multiple sclerosis

The experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis was used in combination with a Cav1.2 conditional knock-out mouse (Cav1.2KO) to study the role of astrocytic voltage-gated Ca++ channels in autoimmune CNS inflammation and demyelination. Cav1.2 channels were specifically ablated in Glast-1-positive astrocytes by means of the Cre-lox system before EAE induction. After immunization, motor activity was assessed daily, and a clinical score was given based on the severity of EAE symptoms. Cav1.2 deletion in astrocytes significantly reduced the severity of the disease. While no changes were found in the day of onset and peak disease severity, EAE mean clinical score was lower in Cav1.2KO animals during the chronic phase of the disease. This corresponded to better performance on the rotarod and increased motor activity in Cav1.2KO mice. Furthermore, decreased numbers of reactive astrocytes, activated microglia, and infiltrating lymphocytes were found in the lumbar section of the spinal cord of Cav1.2KO mice 40 days after immunization. The degree of myelin protein loss and size of demyelinated lesions were also attenuated in Cav1.2KO spinal cords. Similar results were found in EAE animals treated with nimodipine, a Cav1.2 Ca++ channel inhibitor with high affinity to the CNS. Mice injected with nimodipine during the acute and chronic phases of the disease exhibited lower numbers of reactive astrocytes, activated microglial, and infiltrating immune cells, as well as fewer demyelinated lesions in the spinal cord. These changes were correlated with improved clinical scores and motor performance. In summary, these data suggest that antagonizing Cav1.2 channels in astrocytes during EAE alleviates neuroinflammation and protects the spinal cord from autoimmune demyelination.

Interferon-γ controls aquaporin 4-specific Th17 and B cells in neuromyelitis optica spectrum disorder.

Neuromyelitis optica spectrum disorder (NMOSD) is a CNS autoimmune inflammatory disease mediated by T helper 17 (Th17) and antibody responses to the water channel protein, aquaporin 4 (AQP4), and associated with astrocytopathy, demyelination and axonal loss. Knowledge about disease pathogenesis is limited and the search for new therapies impeded by the absence of a reliable animal model. In our work, we determined that NMOSD is characterized by decreased IFN-γ receptor signalling and that IFN-γ depletion in AQP4201-220-immunized C57BL/6 mice results in severe clinical disease resembling human NMOSD. Pathologically, the disease causes autoimmune astrocytic and CNS injury secondary to cellular and humoral inflammation. Immunologically, the absence of IFN-γ allows for increased expression of IL-6 in B cells and activation of Th17 cells, and generation of a robust autoimmune inflammatory response. Consistent with NMOSD, the experimental disease is exacerbated by administration of IFN-β, whereas repletion of IFN-γ, as well as therapeutic targeting of IL-17A, IL-6R and B cells, ameliorates it. We also demonstrate that immune tolerization with AQP4201-220-coupled poly(lactic-co-glycolic acid) nanoparticles could both prevent and effectively treat the disease. Our findings enhance the understanding of NMOSD pathogenesis and provide a platform for the development of immune tolerance-based therapies, avoiding the limitations of the current immunosuppressive therapies.

Clinical characteristics of patient with GFAP-IgG: A Review of 31 Patients from Two Tertiary Referral Centers in China

ABSTRACT Objective This study presents a comprehensive analysis of the clinical characteristics of 31 patients exhibiting cerebrospinal fluid (CSF) and/or serum positivity for GFAP-IgG, with a specific emphasis on 24 cases demonstrating only GFAP-IgG positivity. The investigation thoroughly evaluates their clinical, radiological, and laboratory features, as well as treatment responses, with the objective of offering clinicians potential diagnostic and therapeutic approaches. Methods A total of 31 patients with GFAP-IgG in the CSF and/or serum were registered between August 2016 and August 2021 at the General Hospital of Ningxia Medical University and Huashan Hospital of Fudan University. We retrospectively reviewed their clinical records. Results Overall, the patients were positive with GFAP-IgG in their CSF (15/31), in serum (6/31), and both CSF and serum (10/31). Among them, two were eventually diagnosed with astroglioma and primary central nervous system lymphoma, respectively; one patient had typical multiple sclerosis; three exhibited overlapping GFAP-IgG and aquaporin-4-IgG (AQP4-IgG); and one patient was coexisting N-Methyl-D-aspartate receptor IgG. The remaining 24 patients were only GFAP-IgG positive. In total, 22 out of the 24 patients had abnormal MRI outcomes, involving the brain, meninges, and spinal cord. Besides, seven of the 24 patients developed optic neuritis. The CSF protein levels positively correlated with the Expanded Disability Status Scale score (EDSSs). Significantly decreased EDSSs, modified Rankin Scale score, GFAP-IgG titer, CSF protein level, and CSF white blood cell counts were observed after immunomodulatory therapy. Conclusion The clinical manifestations of GFAP-IgG exhibit a wide range of phenotypes that lack specificity. These findings emphasize the significance of not exclusively relying on the presence of antibodies to diagnose GFAP-A, but rather integrating them with the clinical phenotypes. GFAP-IgG testing enables the diagnosis of autoimmune GFAP astrocytopathy, a treatable autoimmune disease affecting the central nervous system. This condition provides opportunities for investigating innovative mechanisms of CNS autoimmunity and inflammation.

Orally delivered lactate-producing bacteria limit CNS autoimmunity.

Orally delivered lactate-producing bacteria limit CNS autoimmunity.

Characterization and diagnosis spectrum of patients with cerebrospinal fluid pleocytosis

PurposeThere is an overlap in the cerebrospinal fluid (CSF) characteristics of patients presenting with different etiologies of CSF pleocytosis. Here, we characterized patients with CSF pleocytosis treated in a large hospital.MethodsA retrospective cohort study of 1150 patients with an elevated CSF leukocyte count > 5 cells/µl treated at a university hospital in Germany from January 2015 to December 2017 was performed. Information on clinical presentation, laboratory parameters, diagnosis and outcome was collected. Clinical and laboratory features were tested for their potential to differentiate between bacterial meningitis (BM) and other causes of CSF pleocytosis.ResultsThe most common etiologies of CSF pleocytosis were CNS infections (34%: 20% with detected pathogen, 14% without), autoimmune (21%) and neoplastic diseases (16%). CSF cell count was higher in CNS infections with detected pathogen (median 82 cells/µl) compared to autoimmune (11 cells/µl, p = 0.001), neoplastic diseases (19 cells/µl, p = 0.01) and other causes (11 cells/µl, p < 0.001). The CHANCE score was developed to differentiate BM from other causes of CSF pleocytosis: Multivariate regression revealed that CSF cell count > 100 cells/µl, CSF protein > 100 mg/dl, CRP > 5 mg/dl, elevated white blood cell count, abnormal mental status and nuchal rigidity are important indicators. The CHANCE score identified patients with BM with high sensitivity (92.1%) and specificity (90.9%) (derivation cohort: AUC: 0.955, validation cohort: AUC: 0.956).ConclusionOverall, the most common causes for CSF pleocytosis include infectious, neoplastic or autoimmune CNS diseases in ~ 70% of patients. The CHANCE score could be of help to identify patients with high likelihood of BM and support clinical decision making.

Clinical course features of atypical demyelinating optic neuritis: case series

Optic neuritis (ON) can often occur at the onset of a demyelinating autoimmune CNS disease or as one of its clinical manifestations. The introduction of novel laboratory techniques, technical advances in magnetic resonance imaging (MRI), electrophysiologic studies, and ocular imaging have significantly expanded the spectrum of autoimmune optic neuropathies. Identification of different forms of ON based on clinical and instrumental data can lead to early diagnosis of the underlying neurologic disorder. According to current guidelines, one can distinguish between typical ON, which are mainly associated with multiple sclerosis (MS), and atypical ON, which are the main clinical manifestation of neuromyelitis optica spectrum disorders (NMOSD) and diseases associated with myelin oligodendrocyte glycoprotein antibodies (MOGAD). In this paper, we present four clinical cases of atypical ON at the onset of NMOSD and MOGAD and illustrate the high diagnostic value of a multidisciplinary approach.

Visualizing the activation of encephalitogenic T cells in the ileal lamina propria by in vivo two-photon imaging

Autoreactive encephalitogenic T cells exist in the healthy immune repertoire but need a trigger to induce CNS inflammation. The underlying mechanisms remain elusive, whereby microbiota were shown to be involved in the manifestation of CNS autoimmunity. Here, we used intravital imaging to explore how microbiota affect the T cells as trigger of CNS inflammation. Encephalitogenic CD4+ T cells transduced with the calcium-sensing protein Twitch-2B showed calcium signaling with higher frequency than polyclonal T cells in the small intestinal lamina propria (LP) but not in Peyer's patches. Interestingly, nonencephalitogenic T cells specific for OVA and LCMV also showed calcium signaling in the LP, indicating a general stimulating effect of microbiota. The observed calcium signaling was microbiota and MHC class II dependent as it was significantly reduced in germfree animals and after administration of anti-MHC class II antibody, respectively. As a consequence of T cell stimulation in the small intestine, the encephalitogenic T cells start expressing Th17-axis genes. Finally, we show the migration of CD4+ T cells from the small intestine into the CNS. In summary, our direct in vivo visualization revealed that microbiota induced T cell activation in the LP, which directed T cells to adopt a Th17-like phenotype as a trigger of CNS inflammation.

T cell deletional tolerance restricts AQP4 but not MOG CNS autoimmunity

Aquaporin-4 (AQP4)-specific Th17 cells are thought to have a central role in neuromyelitis optica (NMO) pathogenesis. When modeling NMO, only AQP4-reactive Th17 cells from AQP4-deficient (AQP4-/-), but not wild-type (WT) mice, caused CNS autoimmunity in recipient WT mice, indicating that a tightly regulated mechanism normally ensures tolerance to AQP4. Here, we found that pathogenic AQP4 T cell epitopes bind MHC II with exceptionally high affinity. Examination of T cell receptor (TCR) α/β usage revealed that AQP4-specific T cells from AQP4-/- mice employed a distinct TCR repertoire and exhibited clonal expansion. Selective thymic AQP4 deficiency did not fully restore AQP4-reactive T cells, demonstrating that thymic negative selection alone did not account for AQP4-specific tolerance in WT mice. Indeed, AQP4-specific Th17 cells caused paralysis in recipient WT or B cell-deficient mice, which was followed by complete recovery that was associated with apoptosis of donor T cells. However, donor AQP4-reactive T cells survived and caused persistent paralysis in recipient mice deficient in both T and B cells or mice lacking T cells only. Thus, AQP4 CNS autoimmunity was limited by T cell-dependent deletion of AQP4-reactive T cells. In contrast, myelin oligodendrocyte glycoprotein (MOG)-specific T cells survived and caused sustained disease in WT mice. These findings underscore the importance of peripheral T cell deletional tolerance to AQP4, which may be relevant to understanding the balance of AQP4-reactive T cells in health and in NMO. T cell tolerance to AQP4, expressed in multiple tissues, is distinct from tolerance to MOG, an autoantigen restricted in its expression.

AXL+SIGLEC6+ dendritic cells in cerebrospinal fluid and brain tissues of patients with autoimmune inflammatory demyelinating disease of CNS

Inflammatory demyelinating disease of the CNS (IDD) is a heterogeneous group of autoimmune diseases, and multiple sclerosis is the most common type. Dendritic cells (DCs), major antigen-presenting cells, have been proposed to play a central role in the pathogenesis of IDD. The AXL+SIGLEC6+ DC (ASDC) has been only recently identified in humans and has a high capability of T cell activation. Nevertheless, its contribution to CNS autoimmunity remains still obscure. Here, we aimed to identify the ASDC in diverse sample types from IDD patients and experimental autoimmune encephalomyelitis (EAE). A detailed analysis of DC subpopulations using single-cell transcriptomics for the paired cerebrospinal fluid (CSF) and blood samples of IDD patients (total n = 9) revealed that three subtypes of DCs (ASDCs, ACY3+ DCs, and LAMP3+ DCs) were overrepresented in CSF compared with their paired blood. Among these DCs, ASDCs were also more abundant in CSF of IDD patients than in controls, manifesting poly-adhesional and stimulatory characteristics. In the brain biopsied tissues of IDD patients, obtained at the acute attack of disease, ASDC were also frequently found in close contact with T cells. Lastly, the frequency of ASDC was found to be temporally more abundant in acute attack of disease both in CSF samples of IDD patients and in tissues of EAE, an animal model for CNS autoimmunity. Our analysis suggests that the ASDC might be involved in the pathogenesis of CNS autoimmunity.

HNF4α, SP1 and c-myc are master regulators of CNS autoimmunity

Hepatocyte nuclear factor 4 α (HNF4α), a transcription factor (TF) essential for embryonic development, has been recently shown to regulate the expression of inflammatory genes. To characterize HNF4a function in immunity, we measured the effect of HNF4α antagonists on immune cell responses in vitro and in vivo. HNF4α blockade reduced immune activation in vitro and disease severity in the experimental model of multiple sclerosis (MS). Network biology studies of human immune transcriptomes unraveled HNF4α together with SP1 and c-myc as master TF regulating differential expression at all MS stages. TF expression was boosted by immune cell activation, regulated by environmental MS risk factors and higher in MS immune cells compared to controls. Administration of compounds targeting TF expression or function demonstrated non-synergic, interdependent transcriptional control of CNS autoimmunity in vitro and in vivo. Collectively, we identified a coregulatory transcriptional network sustaining neuroinflammation and representing an attractive therapeutic target for MS and other inflammatory disorders.

Immunoresponsive Gene 1: an important regulator of autoreactive CD4 +T Cells in mouse model of multiple sclerosis

Abstract Th17 and Th1 CD4 T cells play important roles in the pathophysiology of human MS and the mouse model of MS, experimental autoimmune encephalomyelitis (EAE). As per our findings, metabolic changes in MS alter the phenotypic and functionality of immune cells, which may influence their effector activities as disease progresses. IRG1 (Immuno response gene 1), encodes for cis-aconitic acid decarboxylase in TCA cycle &amp; enhances the manufacture of mitochondria-selective metabolite, itaconic acid from cis-aconitate, is one such gene linking metabolism to immune effector function. It modulates inflammation in myeloid cells in addition to its antibacterial activity. The relevance of IRG1 in CNS autoimmunity, however, is still unknown. We used IRG1 KO mice to know what role it plays in EAE. We observed that global IRG1 KO showed significantly worsened clinical disease severity compared to their WT at the peak of the disease (3.3+0.50 vs. 2.1+0.50, p&amp;lt; 0.05). We found an evident early onset of disease induction &amp; severity in the IRG1 KO as compared to the Wt (D9 vs. D13). Furthermore, to examine the mechanism of EAE pathogenesis, found a significantly higher infiltration of CD45 hicells (mainly Th17/Th1 cells) in the CNS of IRG1 KO mice compared to Wt mice. Adoptive transfer of CD45+ cells from immunized IRG1 KO augmented the disease progression in RAG1 deficient mice suggesting a possible role of IRG1 in a hyperactivated Th17 response. Also, itaconate treatment at the dose of 15mg/kg bw attenuated EAE disease relapse in SJL mice. Our findings suggest that IRG1/itaconate negatively regulates the Th17 immune response &amp; moDCs’ function to attenuate the EAE disease progression, which may open a novel therapeutic avenue in the development of MS-related therapies.

MHV-68 induces central nervous system autoimmunity in an MBP-specific TCR transgenic mouse model of multiple sclerosis

Abstract Multiple Sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system. Latent infection with Epstein-Barr virus (EBV) has been identified as a necessary yet insufficient factor in the development of the disease. Several groups have demonstrated that the murine EBV analogue, MHV-68, exacerbates disease severity in experimental autoimmune encephalomyelitis (EAE). However, the induction of EAE requires immunization and does not fully replicate the clinical features of MS. We sought to develop a virus-inducible model that accurately represents MS etiology and does not rely on classical EAE immunization. Using a transgenic mouse line with a myelin basic protein-specific T cell receptor, we found that MHV-68 induces demyelinating disease in 72% of infected mice. These mice exhibit clinical features such as optic neuritis, incontinence, and head tilt, which are commonly observed in MS patients but not in mice with EAE. This phenomenon was specific to MHV-68 and was not seen with other viral pathogens including PR8 influenza. Our work demonstrates that latent gammaherpesvirus infection can drive CNS autoimmunity in genetically predisposed mice without prior EAE induction, thus providing a more natural murine model of MS. National Institute of Health R01AI140741-04

An IL-23/STAT4 axis regulates classical dendritic cell expansion and function in CNS autoimmunity

Abstract Signal transducer and activator of transcription 4 (STAT4) is a critical regulator of inflammation in autoimmunity by acting as a messenger for pro-inflammatory cytokines including IL-12 and IL-23. In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, germ-line deletion of STAT4 in mice results in resistance to the development of paralysis. Here, we examined STAT4 cell-specific requirements in EAE. Using conditional Stat4mutant mice, we found that mice lacking Stat4in CD4 +T cells and CD11c +cells are resistant to EAE, while Lyz2 +cells are susceptible to EAE demonstrating cell type requirement for STAT4 in EAE. STAT4 is expressed and activated in CD11c +classical dendritic cells (cDCs) in the CNS at the peak of EAE. Stat4fl/flCD11cCre(Stat4ΔCD11c) mice exhibit a significant decrease of cDC expansion in the CNS, and this correlates with diminished numbers of T cells in the CNS and decreased inflammatory cytokine production. Adoptive transfer of wild-type DCs into Stat4ΔCD11crescues the development of EAE. In contrast, transferring Il23r−/−DCs to Stat4ΔCD11cdid not rescue EAE development. Transferred Il23r−/−DCs were retained in the lymph nodes suggesting that IL-23-STAT4 signaling in cDCs promotes their expansion in the CNS during neuroinflammation. CITE-seq analysis of CNS DCs from control and Stat4ΔCD11cmice identified STAT4-dependent genes in cDCs in EAE. Collectively, our results demonstrate that STAT4 in cDCs is required for their expansion in the CNS, the development of pro-inflammatory T cells, and the clinical symptoms of EAE. Thus, our study reveals previously unrecognized functions of STAT4 in cDCs that could identify novel therapeutic approaches for CNS autoimmunity.

Intrinsic STAT4 Expression Controls Effector CD4 T Cell Migration and Th17 Pathogenicity.

Effector CD4 T cells are central to the development of autoimmune chronic inflammatory diseases, yet factors that mediate pathogenicity remain ill-defined. Single-nucleotide polymorphisms in the human STAT4 locus are associated with susceptibility to multiple autoimmune disorders, and Stat4 is linked to the pathogenic Th17 gene signature; however, Th17 cells differentiate independently of STAT4. Hence the interplay between STAT4 and CD4 T cell function, especially Th17 cells, during autoimmune disease is unclear. In this article, we demonstrate that CD4 T cell-intrinsic STAT4 expression is essential for the induction of autoimmune CNS inflammation in mice, in part by regulating the migration of CD4 T cells to the inflamed CNS. Moreover, unbiased transcriptional profiling revealed that STAT4 controls the expression of >200 genes in Th17 cells and is important for the upregulation of genes associated with IL-23-stimulated, pathogenic Th17 cells. Importantly, we show that Th17 cells specifically require STAT4 to evoke autoimmune inflammation, highlighting, to our knowledge, a novel function for STAT4 in Th17 pathogenicity.

Origins and immunopathogenesis of autoimmune central nervous system disorders.

The field of autoimmune neurology is rapidly evolving, and recent discoveries have advanced our understanding of disease aetiologies. Inthis article, we review the key pathogenic mechanisms underlying the development of CNS autoimmunity. First, we review non-modifiable risk factors, such as age, sex and ethnicity, as well as genetic factors such as monogenic variants, common variants in vulnerability genes and emerging HLA associations. Second, we highlight how interactions between environmental factors and epigenetics can modify disease onset and severity. Third, we review possible disease mechanisms underlying triggers that are associated with the loss of immune tolerance with consequent recognition of self-antigens; these triggers include infections, tumours and immune-checkpoint inhibitor therapies. Fourth, we outline how advances in our understanding of the anatomy of lymphatic drainage and neuroimmune interfaces are challenging long-held notions of CNS immune privilege, with direct relevance to CNS autoimmunity, and how disruption of B cell and T cell tolerance and the passage of immune cells between the peripheral and intrathecal compartments have key roles in initiating disease activity. Last, we consider novel therapeutic approaches based on our knowledge of the immunopathogenesis of autoimmune CNS disorders.

GPR52 regulates cAMP in T cells but is dispensable for encephalitogenic responses.

G-protein coupled receptors (GPCR) regulate 3',5'-cyclic adenosine monophosphate (cAMP) levels in T cells. cAMP as ubiquitous second messenger is crucial for adequate physiology of T cells by mediating effector T cell (Teff) function as well as regulatory T cell (Treg)-mediated immunosuppression. Several GPCRs have been identified to be crucial for Teff and Treg function. However, the role of the orphan, constitutively active Gs-coupled GPCR GPR52 is unknown. Here we show that GPR52 regulates cAMP levels in T cells but does not affect T cell function. We found that stimulation of transfected HEK cells or primary T cells with a GPR52 agonist results in a rise of intracellular cAMP. However, neither Gpr52 deficiency nor pharmacological modulation of GPR52 by antagonists or agonists affected T cell activation, differentiation, and proliferation or Treg-mediated immunosuppression. Moreover, Gpr52 deletion did not modify the clinical disease course of experimental autoimmune encephalomyelitis (EAE). Our results demonstrate that a modulation of cAMP levels in T cells does not inevitably result in altered T cell function. While we could not identify an obvious role of GPR52 in in vitro T cell assays and in vivo CNS autoimmunity, it might regulate T cell function in a different context or affect the function of other GPR52-expressing cells.