Cytokines in sural nerve biopsies from inflammatory and non-inflammatory neuropathies

Lindenlaub, Thies; Sommer, Claudia

doi:10.1007/s00401-003-0689-y

Cited by 151 publications

(71 citation statements)

References 20 publications

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“…Schwann cells were shown to consistently express adhesion/T-cell stimulatory molecule CD58 (LFA-3) in CIDP, with high CD74 (associates with MHC Class II serving as a chaperone for antigen presentation) in both CIDP and control nerves. ICAM-1 expression on CIDP and healthy control endoneurial microvessels was also observed consistently [81,74,140]. …”

Section: Introductionmentioning

confidence: 88%

“…Increased sural nerve expression of IL1-β, IL-6, and TNF-α has been described in vasculitic neuropathy, with immunoreactivity directly correlated with the degree of axonal degeneration, endoneurial macrophages and epineurial T cells and neuropathic pain [74]. Expression of MMP-9, was increased in perivascular inflammatory infiltrate in nerve tissues of vasculitic neuropathy patients, with variable MMP-2 expression that may be expressed by stromal perineurial and epineurial cells [71].…”

Section: Introductionmentioning

confidence: 99%

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Inflammatory neuropathies: pathology, molecular markers and targets for specific therapeutic intervention

Ubogu

2015

Acta Neuropathol

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Inflammatory neuropathies encompass groups of heterogeneous disorders characterized by pathogenic immune-mediated hematogenous leukocyte infiltration of peripheral nerves, nerve roots or both, with resultant demyelination or axonal degeneration or both. Inflammatory neuropathies may be divided into three major disease categories: Guillain-Barré syndrome (particularly the acute inflammatory demyelinating polyradiculoneuropathy variant), Chronic inflammatory demyelinating polyradiculoneuropathy and nonsystemic vasculitic neuropathy (or peripheral nerve vasculitis). Despite major advances in molecular biology, pathology and genetics, the pathogenesis of these disorders remains elusive. There is insufficient knowledge on the mechanisms of hematogenous leukocyte trafficking into the peripheral nervous system to guide the development of specific molecular therapies for immune-mediated inflammatory neuropathies compared to disorders such as psoriasis, inflammatory bowel disease, rheumatoid arthritis or multiple sclerosis. The recent isolation and characterization of human endoneurial endothelial cells that form the blood-nerve barrier provides an opportunity to elucidate leukocyte-endothelial cell interactions critical to the pathogenesis of inflammatory neuropathies at the interface between the systemic circulation and peripheral nerve endoneurium. This review discusses our current knowledge of the classic pathological features of inflammatory neuropathies, attempts at molecular classification and genetic determinants, the utilization of in vitro and in vivo animal models to determine pathogenic mechanisms at the interface between the systemic circulation and the peripheral nervous system relevant to these disorders and prospects for future potential molecular pathology biomarkers and targets for specific therapeutic intervention.

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Section: Introductionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Inflammatory neuropathies: pathology, molecular markers and targets for specific therapeutic intervention

Ubogu

2015

Acta Neuropathol

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“…Physiological endothelial cytokine treatment induced a mean 2.13-fold increase in CIDP PBML AMI (range 1.23–2.84; Figure 1), implying an important role of local inflammatory cascades (e.g. upregulation in cytokines, chemokines, selectins and cell adhesion molecules) (Dalakas and Medscape, 2011; Lindenlaub and Sommer, 2003; Mathey et al, 1999; Press et al, 2003; Ubogu, 2015) in driving pathogenic CIDP patient PBML trafficking at the BNB in vitro , as demonstrated with Guillain-Barré syndrome patients (Yosef and Ubogu, 2012). …”

Section: Resultsmentioning

confidence: 99%

“…Pro-inflammatory cytokine expression (TNF-α, IFN- γ, interleukin-1, interleukin-2 and interleukin-6) in active CIDP patient sural nerves localizing to the innermost layer of the perineurium, epineurial and endoneurial blood vessels, infiltrating inflammatory cells and possibly Schwann cells has been described relative to control patient nerves (providing rationale for physiological cytokine stimulation of the in vitro BNB leukocyte trafficking model) (Lindenlaub and Sommer, 2003; Mathey et al, 1999; Van Rhijn et al, 2000). Endoneurial monocytes/macrophages (the most common leukocyte subset), CD4+ and CD8+ T-lymphocytes are seen at higher numbers in CIDP nerves compared to controls (Krendel et al, 1989; Schmidt et al, 1996; Ubogu, 2015).…”

Section: Discussionmentioning

confidence: 99%

Fibronectin connecting segment-1 peptide inhibits pathogenic leukocyte trafficking and inflammatory demyelination in experimental models of chronic inflammatory demyelinating polyradiculoneuropathy

Dong

Greathouse

Beacham

et al. 2017

Experimental Neurology

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The molecular determinants of pathogenic leukocyte migration across the blood-nerve barrier (BNB) in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) are unknown. Specific disease modifying therapies for CIDP are also lacking. Fibronectin connecting segment-1 (FNCS1), an alternatively spliced fibronectin variant expressed by microvascular endothelial cells at sites of inflammation in vitro and in situ, is a counterligand for leukocyte α4 integrin (also known as CD49d) implicated in pathogenic leukocyte trafficking in multiple sclerosis and inflammatory bowel disease. We sought to determine the role of FNCS1 in CIDP patient leukocyte trafficking across the BNB in vitro and in severe chronic demyelinating neuritis in vivo using a representative spontaneous murine CIDP model. Peripheral blood mononuclear leukocytes from 7 untreated CIDP patients were independently infused into a cytokine-treated, flow-dependent in vitro BNB model system. Time-lapse digital video microscopy was performed to visualize and quantify leukocyte trafficking, comparing FNCS1 peptide blockade to relevant controls. Fifty 24-week old female B7-2 deficient non-obese diabetic mice with spontaneous autoimmune peripheral polyneuropathy (SAPP) were treated daily with 2 mg/kg FNCS1 peptide for 5 days via intraperitoneal injection with appropriate controls. Neurobehavioral measures of disease severity, motor nerve electrophysiology assessments and histopathological quantification of inflammation and morphometric assessment of demyelination were performed to determine in vivo efficacy. The biological relevance of FNCS1 and CD49d in CIDP was evaluated by immunohistochemical detection in affected patient sural nerve biopsies. 25 μM FNCS1 peptide maximally inhibited CIDP leukocyte trafficking at the human BNB in vitro. FNCS1 peptide treatment resulted in significant improvements in disease severity, motor electrophysiological parameters of demyelination and histological measures of inflammatory demyelination. Microvessels demonstrating FNCS1 expression and CD49d+ leukocytes were seen within the endoneurium of patient nerve biopsies. Taken together, these results imply a role for FNCS1 in pathogenic leukocyte trafficking in CIDP, providing a potential target for therapeutic modulation.

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“…10–13 This process of peripheral sensitization is thought to play a key role in the maintenance of local pain in conditions such as painful TMD. Results from clinical studies demonstrate that proinflammatory cytokine levels are elevated in individuals with painful TMD, 9,14–17 headache, IBS, 18–20 pelvic pain, 18,21,22 and widespread pain. 12,23–26 …”

Section: Introductionmentioning

confidence: 99%

Circulating Omentin-1 and Chronic Painful Temporomandibular Disorders

Harmon¹,

Sanders²,

Wilder³

et al. 2016

J Oral Facial Pain Headache

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AIMS The biological basis for painful temporomandibular disorder (TMD) remains unclear. An emerging literature implicates circulating inflammatory cytokines in the development of pain sensitivity and painful TMD. One newly discovered anti-inflammatory adipokine, omentin-1, has decreased expression in several inflammatory conditions including osteoarthritis. The aim of this study was to investigate the relationship between omentin-1 levels and painful TMD. METHODS Using a case-control design, chronic painful TMD cases (n=90) and TMD-free controls (n=54) were selected participants in the multisite OPPERA study (Orofacial Pain: Prospective Evaluation and Risk Assessment). Painful TMD case status was determined by examiner using established Research Diagnostic Criteria for TMD. Levels of omentin-1 were measured in stored blood plasma samples using an enzyme-linked immunosorbent assay. Binary logistic regression calculated the odds ratios (ORs) and 95% confidence limits (CLs) for the association between omentin-1 and painful TMD. Models adjusted for study site, age, sex, and body mass index (BMI). RESULTS The unadjusted association between omentin-1 and chronic painful TMD was statistically non-significant (P=.072) Following adjustment of the negative confounding bias of covariates, odds of painful decreased 36% per standard deviation increase in circulating omentin-1 (adjusted OR=0.64, 95% CL: 0.43, 0.96. P=.031). CONCLUSION Circulating levels of omentin-1 were significantly lower in painful TMD cases than controls, suggesting that painful TMD pain is mediated by inflammatory pathways.

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Cytokines in sural nerve biopsies from inflammatory and non-inflammatory neuropathies

Cited by 151 publications

References 20 publications

Inflammatory neuropathies: pathology, molecular markers and targets for specific therapeutic intervention

Inflammatory neuropathies: pathology, molecular markers and targets for specific therapeutic intervention

Fibronectin connecting segment-1 peptide inhibits pathogenic leukocyte trafficking and inflammatory demyelination in experimental models of chronic inflammatory demyelinating polyradiculoneuropathy

Circulating Omentin-1 and Chronic Painful Temporomandibular Disorders

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