Cytokine/chemokine levels in the CSF and serum of anti-NMDAR encephalitis: A systematic review and meta-analysis

Ma, Yu; Wang, Jierui; Guo, S.; Meng, Zhiyi; Ren, Yan; Wang, Minjin

doi:10.3389/fimmu.2022.1064007

Cited by 12 publications

(7 citation statements)

References 77 publications

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“…Interestingly, CXCL13 was identified as a biomarker with the highest predictive utility for the general recognition of neuroinflammation in the particular cohort [54]. Recently, a systematic review and meta-analysis by Ma et al (2023) [55] showed increased CSF concentrations of CXCL10 in patients with anti-Nmethyl-D-aspartate receptor encephalitis (NMDAR-E) compared with patients presenting with non-inflammatory neurological disorders, suggesting its possible diagnostic value in this model as well.…”

Section: Discussionmentioning

confidence: 99%

Proinflammatory Chemokine Levels in Cerebrospinal Fluid of Patients with Neuroinvasive Flavivirus Infections

Zidovec-Lepej,

Bodulić,

Bogdanic

et al. 2024

Microorganisms

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Tick-borne encephalitis virus (TBEV) and West Nile virus (WNV) are the most important neuroinvasive arboviruses detected in Europe. In this study, we analyzed cerebrospinal fluid (CSF) concentrations of 12 proinflammatory chemokines (CCL2, CCL3, CCL4, CCL11, CCL17, CCL20, CXCL1, CXCL5, CXCL8, CXCL9, CXCL10, and CXCL11) in 77 patients with neuroinvasive diseases (NIDs). Flavivirus infection was confirmed in 62 patients (TBEV and WNV in 31 patients each), while in 15 patients the etiology of NID was not determined (NDE). Similar patterns of high-level expression of chemokines regulating monocyte/macrophage responses (CCL2), neutrophil recruitment (CXCL1 and CXCL8), and interferon-inducible chemoattractants for leukocytes (CXCL10 and CXCL11) have been observed in WNV and TBEV groups. None of the tested chemokines significantly differed between patients with TBEV or WNV. Concentrations of CCL17, CCL20, CXCL5, CXCL10, and CXCL11 were significantly lower in both WNV and TBEV groups compared to NID NDE patients. The logistic regression model showed that CSF concentrations of CXCL11, CXCL5, and CXCL10 could potentially be used for the classification of patients into the WNV or TBEV group versus groups with other NIDs. This study identified, for the first time, similar patterns of CSF chemokine expression in WNV and TBEV infections, suggesting common immunopathogenic mechanisms in neuroinvasive flavivirus infections that should be further evaluated.

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Section: Discussionmentioning

confidence: 99%

Proinflammatory Chemokine Levels in Cerebrospinal Fluid of Patients with Neuroinvasive Flavivirus Infections

Zidovec-Lepej,

Bodulić,

Bogdanic

et al. 2024

Microorganisms

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“…Ventrally-induced mice also demonstrated decreased hippocampal NMDARs and intracerebral T cells and plasma cells 4 weeks after immunization. A recent metanalysis of cytokines from the blood and spinal fluid of NMDARE patients ( 5 ) demonstrated a predominance of T-cell-associated cytokines, along with some B-cell-related and broad-spectrum cytokines in the CSF of NMDARE patients, as compared to controls. There were elevations of IFN-γ, IL-1β, TNF-α, IL-6, IL-10, and IL-12 noted in NMDARE patients’ spinal fluid, cytokines which were included in the commercial pro-inflammatory kit we used.…”

Section: Discussionmentioning

confidence: 99%

“…However, the diagnosis and treatment of AE are currently hampered by an incomplete understanding of its pathogenesis. This is partly due to limited autopsy data ( 4 ) and relatively few immune-based studies in patients, such as cytokine profiling ( 5 ). As AE remains a comparatively rare disorder, translational animal models are needed to better elucidate its pathophysiology, which can lead to novel diagnostics and therapeutics.…”

Section: Introductionmentioning

confidence: 99%

Optimizing animal models of autoimmune encephalitis using active immunization

et al. 2023

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Background and objectivesEncephalitis is a devastating neurologic disorder with high morbidity and mortality. Autoimmune causes are roughly as common as infectious ones. N-methyl-D-aspartic acid receptor (NMDAR) encephalitis (NMDARE), characterized by serum and/or spinal fluid NMDAR antibodies, is the most common form of autoimmune encephalitis (AE). A translational rodent NMDARE model would allow for pathophysiologic studies of AE, leading to advances in the diagnosis and treatment of this debilitating neuropsychiatric disorder. The main objective of this work was to identify optimal active immunization conditions for NMDARE in mice.MethodsFemale C57BL/6J mice aged 8 weeks old were injected subcutaneously with an emulsion of complete Freund’s adjuvant, killed and dessicated Mycobacterium tuberculosis, and a 30 amino acid peptide flanking the NMDAR GluN1 subunit N368/G369 residue targeted by NMDARE patients’ antibodies. Three different induction methods were examined using subcutaneous injection of the peptide emulsion mixture into mice in 1) the ventral surface, 2) the dorsal surface, or 3) the dorsal surface with reimmunization at 4 and 8 weeks (boosted). Mice were bled biweekly and sacrificed at 2, 4, 6, 8, and 14 weeks. Serum and CSF NMDAR antibody titer, mouse behavior, hippocampal cell surface and postsynaptic NMDAR cluster density, and brain immune cell entry and cytokine content were examined.ResultsAll immunized mice produced serum and CSF NMDAR antibodies, which peaked at 6 weeks in the serum and at 6 (ventral and dorsal boosted) or 8 weeks (dorsal unboosted) post-immunization in the CSF, and demonstrated decreased hippocampal NMDAR cluster density by 6 weeks post-immunization. In contrast to dorsally-immunized mice, ventrally-induced mice displayed a translationally-relevant phenotype including memory deficits and depressive behavior, changes in cerebral cytokines, and entry of T-cells into the brain at the 4-week timepoint. A similar phenotype of memory dysfunction and anxiety was seen in dorsally-immunized mice only when they were serially boosted, which also resulted in higher antibody titers.DiscussionOur study revealed induction method-dependent differences in active immunization mouse models of NMDARE disease. A novel ventrally-induced NMDARE model demonstrated characteristics of AE earlier compared to dorsally-induced animals and is likely suitable for most short-term studies. However, boosting and improving the durability of the immune response might be preferred in prolonged longitudinal studies.

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“…Moreover, anti IL-6 agents can be used in conjunction with mycophenolate mofetil and azathioprine in a relatively safe way, as seen in NMOSD trial (SakuraSky). Given that IL-6 has been shown to be elevated in the CSF of many subtypes of AE ( 73 ), it has been therapeutically trialed in several types of autoimmune encephalitis. In a large institutional cohort of patients with refractory to rituximab AE, the tocilizumab group showed more frequent favorable mRS scores at 2 months from treatment initiation and at the last follow-up compared with the other groups.…”

Section: Il-6 Modulation In Autoimmune Encephalitismentioning

confidence: 99%

Interleukin 6: at the interface of human health and disease

Grebenciucova,

VanHaerents

2023

Front. Immunol.

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Interleukin 6 (IL-6) is a pleiotropic cytokine executing a diverse number of functions, ranging from its effects on acute phase reactant pathways, B and T lymphocytes, blood brain barrier permeability, synovial inflammation, hematopoiesis, and embryonic development. This cytokine empowers the transition between innate and adaptive immune responses and helps recruit macrophages and lymphocytes to the sites of injury or infection. Given that IL-6 is involved both in the immune homeostasis and pathogenesis of several autoimmune diseases, research into therapeutic modulation of IL-6 axis resulted in the approval of a number of effective treatments for several autoimmune disorders like neuromyelitis optica spectrum disorder (NMOSD), rheumatoid arthritis, juvenile idiopathic arthritis, polyarticular juvenile idiopathic arthritis, giant cell arteritis (GCA), and cytokine release syndrome, associated with SARS-CoV2 pneumonia. This review discusses downstream inflammatory pathways of IL-6 expression and therapeutic applications of IL-6 blockade, currently investigated for the treatment of several other autoimmune conditions such as autoimmune encephalitis, autoimmune epilepsy, as well as myelin oligodendrocyte glycoprotein associated demyelination (MOGAD). This review further highlights the need for clinical trials to evaluate IL-6 blockade in disorders such neuropsychiatric lupus erythematosus (SLE), sarcoidosis and Behcet’s.

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Cytokine/chemokine levels in the CSF and serum of anti-NMDAR encephalitis: A systematic review and meta-analysis

Cited by 12 publications

References 77 publications

Proinflammatory Chemokine Levels in Cerebrospinal Fluid of Patients with Neuroinvasive Flavivirus Infections

Proinflammatory Chemokine Levels in Cerebrospinal Fluid of Patients with Neuroinvasive Flavivirus Infections

Optimizing animal models of autoimmune encephalitis using active immunization

Interleukin 6: at the interface of human health and disease

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