From Systemic Inflammation to Neuroinflammation: The Case of Neurolupus

Bendorius, Mykolas; Po, Chrystelle; Muller, Sylviane; Jeltsch-David, Hélène

doi:10.3390/ijms19113588

Cited by 59 publications

(42 citation statements)

References 265 publications

(345 reference statements)

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“…Interestingly, in our study, we found a decline in the hippocampus volume in patients with lupus correlating with fatigue and circulating anti-NMDAR antibody titres over a 2-year time period. Clearly, the impact of anti-NMDAR antibodies on ‘Neuro-Lupus’ may be one factor in a complex pathophysiology involving microglia, cytokines and T cells 42…”

Section: Discussionmentioning

confidence: 99%

Fatigue in SLE: diagnostic and pathogenic impact of anti-N-methyl-D-aspartate receptor (NMDAR) autoantibodies

et al. 2019

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ObjectivesWe explored the impact of circulating anti-N-methyl-D-aspartate receptor (NMDAR) antibodies on the severity of fatigue in patients with systemic lupus erythematosus (SLE).MethodsSerum samples of 426 patients with SLE were analysed for the presence of antibodies to the NR2 subunit of the NMDAR. In parallel, the severity of fatigue was determined according to the Fatigue Scale for Motor and Cognitive functions questionnaire. In a subgroup of patients with SLE, the hippocampal volume was correlated with the levels of anti-NR2 antibodies. Isolated immunoglobulin G from patients with anti-NR2 antibodies were used for murine immunohistochemical experiments and functional assays on neuronal cell lines. Treatment effects were studied in 86 patients with lupus under belimumab therapy.ResultsWe found a close correlation between the titre of anti-NR2 antibodies, the severity of fatigue, the clinical disease activity index (Systemic Lupus Erythematosus Disease Activity Index 2000) and anti-double stranded DNA antibodies—independently of the presence of neuropsychiatric lupus manifestations. Pathogenic effects could be demonstrated by (1) detection of anti-NR2 antibodies in the cerebrospinal fluid, (2) in situ binding of anti-NR2 antibodies to NMDAR of the hippocampus area and (3) distinct functional effects in vitro: downregulating the energy metabolism of neuronal cells without enhanced cytotoxicity. Treatment with belimumab for at least 6 months affected both the severity of fatigue and the levels of anti-NR2 antibodies.ConclusionThe presence of anti-NR2 antibodies in patients with SLE with fatigue is a helpful diagnostic tool and may offer a major approach in the therapeutic management of this important disabling symptom in patients with SLE.

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Section: Discussionmentioning

confidence: 99%

Fatigue in SLE: diagnostic and pathogenic impact of anti-N-methyl-D-aspartate receptor (NMDAR) autoantibodies

et al. 2019

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“…Of note, P140 has been assayed in animal models mimicking other autoimmune and inflammatory conditions. Specially, it was found to be efficient in murine models of neuropsychiatric lupus [133,134], and chronic inflammatory demyelinating polyradiculoneuropathy [135]. P140 also showed remarkable effects on the salivary glands of model mice that develop a secondary Sjögren’s syndrome that is especially characterized in patients by symptoms of extensive dry eyes (xerophthalmia) and dry mouth (xerostomia) [129].…”

Section: Hspa8/hspa8 As a Therapeutic Target In Clinical Trialsmentioning

confidence: 99%

HSPA8/HSC70 in Immune Disorders: A Molecular Rheostat that Adjusts Chaperone-Mediated Autophagy Substrates

Bonam

Ruff²,

Muller

2019

Cells

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HSPA8/HSC70 is a molecular chaperone involved in a wide variety of cellular processes. It plays a crucial role in protein quality control, ensuring the correct folding and re-folding of selected proteins, and controlling the elimination of abnormally-folded conformers and of proteins daily produced in excess in our cells. HSPA8 is a crucial molecular regulator of chaperone-mediated autophagy, as a detector of substrates that will be processed by this specialized autophagy pathway. In this review, we shortly summarize its structure and overall functions, dissect its implication in immune disorders, and list the known pharmacological tools that modulate its functions. We also exemplify the interest of targeting HSPA8 to regulate pathological immune dysfunctions.

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“…While the phrase systemic inflammation is sometimes used as a broad term to point to a causal systemic autoimmune response, we use this term here as a means of indicating the presence of increased levels of blood APRs, as these are sensitive biomarkers of systemic infectious processes that activate innate and adaptive immunity. As it has been observed that some peripheral immune-mediated diseases can induce inflammation in the CNS (12), we additionally addressed the question that if MS patients do indeed have increased levels of peripheral APRs compared to HD, whether or not this systemic inflammation at least partially influences activation of innate and adaptive immunity in the CNS. Finally, we assessed the possible pathogenic role of systemic or intrathecal inflammation by correlating inflammatory biomarkers with MS severity, defined as speed of accumulation of MS disability.…”

Section: Introductionmentioning

confidence: 99%

Intrathecal, Not Systemic Inflammation Is Correlated With Multiple Sclerosis Severity, Especially in Progressive Multiple Sclerosis

et al. 2019

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Objective: To test the hypothesis that Multiple Sclerosis (MS) patients have increased peripheral inflammation compared to healthy donors and that this systemic activation of the immune system, reflected by acute phase reactants (APRs) measured in the blood, contributes to intrathecal inflammation, which in turn contributes to the development of disability in MS.Methods: Eight serum APRs measured in a prospectively-collected cross-sectional cohort with a total of 51 healthy donors and 291 untreated MS patients were standardized and assembled into related biomarker clusters to derive global measures of systemic inflammation. The resulting APR clusters were compared between diagnostic categories and correlated to equivalently-derived cerebrospinal fluid (CSF) biomarkers of innate and adaptive immunity. Finally, correlations were calculated between biomarkers of systemic and intrathecal inflammation and MS severity measures, which predict future rates of disability progression.Results: While two blood APR clusters were elevated in MS patients, only one exhibited a weak correlation with MS severity. All CSF inflammation clusters, except CSF albumin, correlated with at least one measure of MS severity, with biomarkers of humoral adaptive immunity exhibiting the strongest correlations, especially in Progressive MS.Conclusion: Systemic inflammation does not appear to be strongly associated with intrathecal inflammation in MS. Positive correlations between markers of intrathecal inflammation, especially of humoral immunity, with MS severity measures support a pathogenic role of intrathecal (compartmentalized) inflammation in central nervous system tissue destruction, including in Progressive MS.

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From Systemic Inflammation to Neuroinflammation: The Case of Neurolupus

Cited by 59 publications

References 265 publications

Fatigue in SLE: diagnostic and pathogenic impact of anti-N-methyl-D-aspartate receptor (NMDAR) autoantibodies

Fatigue in SLE: diagnostic and pathogenic impact of anti-N-methyl-D-aspartate receptor (NMDAR) autoantibodies

HSPA8/HSC70 in Immune Disorders: A Molecular Rheostat that Adjusts Chaperone-Mediated Autophagy Substrates

Intrathecal, Not Systemic Inflammation Is Correlated With Multiple Sclerosis Severity, Especially in Progressive Multiple Sclerosis

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