The multiple roles of nerve biopsy in the diagnosis and prognosis of suspected immune neuropathies.

INTRODUCTION: The value of a sural nerve biopsy for the diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is controversial. Evidence-based recommendations for its implementation are lacking. We investigated factors leading to biopsy and analyzed biopsy outcomes and consequences, assessed the predictability of biopsy outcomes through clinical parameters to avoid unnecessary biopsies, and compared results with electrophysiological and clinical severity to determine their prognostic value. METHODS: 190 sural nerve biopsies were analyzed in two cohorts. One consisted of 163 biopsies and the second of 72 biopsies from the prospective Immune-mediated Neuropathies Biomaterial and Data registry (INHIBIT). Both have an intersection of 45 patients. 75 data sets from patients without biopsy were used. Analysis of nerve conduction studies, treatment, overall disability sum score (ODSS), biopsy outcomes, and diagnosis was performed. RESULTS: 51% of biopsied patients received the diagnosis CIDP (77% fulfilled EFNS/PNS criteria), 21% were not CIDP typical, and 27% were unspecific. Biopsied patients responded less frequently to immunotherapies at time of biopsy than non-biopsied patients (p = 0.003). Immunotherapy was initiated more frequently after biopsy (p < 0.001) and more often with intravenous immunoglobulins (p < 0.0001). 76% of all biopsied patients met the electrophysiological criteria for CIDP. Sensory nerve action potential amplitudes of 0 µV still provide 73% of histological diagnostic value. Histologic signs of degeneration predicted ODSS worsening after 1 year (p = 0.028) but disease severity did not correlate with histological damage severity. DISCUSSION: The main indication for nerve biopsy was the treatment of refractory cases of autoimmune neuropathies with the therapeutic consequence of treatment initiation or escalation. Sural biopsy also provided prognostic information. Even with extinguished sural SNAP, the biopsy can still have diagnostic value.

Treatment of concomitant myasthenia gravis and Lambert-Eaton myasthenic syndrome with autologous CD19-targeted CAR T cells.

Myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS) are autoimmune disorders affecting neuromuscular transmission. Their combined occurrence is rare, and treatment remains challenging. Two women diagnosed with concomitant MG/LEMS experienced severe, increasing disease activity despite multiple immunotherapies. Anti-CD19 chimeric antigen receptor (CAR) T cells have shown promise for treating autoimmune diseases. This report details the safe application of anti-CD19 CAR T cells for treating concomitant MG/LEMS. After CAR T cell therapy, both patients experienced rapid clinical recovery and regained full mobility. Deep B cell depletion and normalization of acetylcholine receptor and voltage-gated calcium channel N-type autoantibody levels paralleled major neurological responses. Within 2 months, both patients returned to everyday life, from wheelchair dependency to bicycling and mountain hiking, and remain stable at 6 and 4 months post-CAR T cell infusion, respectively. This report highlights the potential for anti-CD19 CAR T cells to achieve profound clinical effects in the treatment of neuroimmunological diseases.

Morphological Differentiation of Corneal Inflammatory Cells: Proposal of Pragmatic Protocol.

PURPOSE: Corneal confocal microscopy is a noninvasive imaging technique to analyze corneal nerve fibers and corneal inflammatory cells (CICs). The amount of CICs is a potential biomarker of disease activity in chronic autoinflammatory diseases. To date, there are no standardized criteria for the morphological characterization of CICs. The aim was to establish a protocol for a standardized morphological classification of CICs based on a literature search and to test this protocol for applicability and reliability. METHODS: A systematic review of the literature about definitions of CICs was conducted. Existing morphological descriptions were translated into a structured algorithm and applied by raters. Subsequently, the protocol was optimized by reducing and defining the criteria of the cell types. The optimized algorithm was applied by 4 raters. The interrater reliability was calculated using Fleiss kappa (K). RESULTS: A systematic review of the literature revealed no uniform morphological criteria for the differentiation of the individual cell types in CICs. Our first protocol achieved only a low level of agreement between 3 raters (K = 0.09; 1062 rated cells). Our revised protocol was able to achieve a higher interrater reliability with 3 (K = 0.64; 471 rated cells) and 4 (K = 0.61; 628 rated cells) raters. CONCLUSIONS: The indirect use of criteria from the literature leads to a high error rate. By clearly defining the individual cell types and standardizing the protocol, reproducible results were obtained, allowing the introduction of this protocol for the future evaluation of CICs in the corneal confocal microscopy.

Small fibre integrity and axonal pathology in the rat model of experimental autoimmune neuritis.

Experimental autoimmune neuritis is a common animal model for acute human immune-mediated polyneuropathies. Although already established in 1955, a number of pathophysiological mechanisms remain unknown. In this study, we extensively characterize experimental autoimmune neuritis progression in Lewis rats, including new insights into the integrity of small nerve fibres, neuropathic pain and macrophage activation. Acute experimental autoimmune neuritis was induced with P253-78 peptide and consequently investigated using the gait analysis system CatWalk XT, electrophysiological and histopathological analyses, quantitative polymerase chain reaction (PCR), dorsal root ganglia outgrowth studies, as well as the von Frey hair and Hargreaves tests. For the longitudinal setup, rats were sacrificed at Day (d) 10 (onset), d15 (peak), d26 (recovery) and d29 (late recovery). We confirmed the classical T-cell and macrophage-driven inflammation and the primarily demyelinating nature of the experimental autoimmune neuritis. The dual role of macrophages in experimental autoimmune neuritis is implicated by the high number of remaining macrophages throughout disease progression. Furthermore, different subpopulations of macrophages based on Cx3-motif chemokine receptor 1 (Cx3cr1), platelet factor 4 (Pf4) and macrophage galactose-type lectin-1 (Mgl1) expressions were identified. In addition, modulation of the sensory system in experimental autoimmune neuritis was detected. An outgrowth of small fibres in the plantar skin at the onset and peak of the experimental autoimmune neuritis was evident parallel to the development of acute hyperalgesia mediated through transient receptor potential vanilloid 1 modulation. Our data depict experimental autoimmune neuritis as a primary demyelinating disease with implicated axonal damage, a small unmyelinated fibre impairment throughout the disease progression course, and underline the pivotal role of macrophages in the effector and during the recovery stage.

Association of the neonatal Fc receptor promoter variable number of tandem repeat polymorphism with immunoglobulin response in patients with chronic inflammatory demyelinating polyneuropathy.

BACKGROUND AND PURPOSE: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease with humoral and cellular autoimmunity causing demyelination of peripheral nerves, commonly treated with intravenous immunoglobulins (IVIg). The neonatal Fc receptor (FcRn), encoded by the FCGRT gene, prevents the degradation of immunoglobulin G (IgG) by recycling circulating IgG. A variable number of tandem repeat (VNTR) polymorphism in the promoter region of the FCGRT gene is associated with different expression levels of mRNA and protein. Thus, patients with genotypes associated with relatively low FcRn expression may show a poorer treatment response to IVIg due to increased IVIg degradation. METHODS: VNTR genotypes were analyzed in 144 patients with CIDP. Patients' clinical data, including neurological scores and treatment data, were collected as part of the Immune-Mediated Neuropathies Biobank registry. RESULTS: Most patients (n = 124, 86%) were VNTR 3/3 homozygotes, and 20 patients (14%) were VNTR 2/3 heterozygotes. Both VNTR 3/3 and VNTR 2/3 genotype groups showed no difference in clinical disability and immunoglobulin dosage. However, patients with a VNTR 2 allele were more likely to receive subcutaneous immunoglobulins (SCIg) than patients homozygous for the VNTR 3 allele (25% vs. 9.7%, p = 0.02) and were more likely to receive second-line therapy (75% vs. 54%, p = 0.05). CONCLUSIONS: The VNTR 2/3 genotype is associated with the administration of SCIg, possibly reflecting a greater benefit from SCIg due to more constant immunoglobulin levels without lower IVIg levels between the treatment circles. Also, the greater need for second-line treatment in VNTR 2/3 patients could be an indirect sign of a lower response to immunoglobulins.

Serum neurofilament light chain does not detect self-reported treatment-related fluctuations in chronic inflammatory demyelinating polyneuropathy.

INTRODUCTION: Serum neurofilament light chain (sNfL) is a marker for axonal degeneration. Patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) often report a fluctuation of symptoms throughout one treatment cycle with intravenous immunoglobulins (IVIG). The aim of this study was to determine whether sNfL is suitable to quantify patient-reported symptom fluctuations. METHODS: Twenty-nine patients with the diagnosis of CIDP or a CIDP-variant under treatment with IVIG were recruited in this study and underwent examination before IVIG infusion, in the middle of the treatment interval, and before their next IVIG infusion. Patients were surveyed regarding symptom fluctuations at the last visit and divided into two groups: those with and without fluctuations of symptoms. At the first visit, sociodemographic and disease-specific data were collected. Clinical scores were assessed at every examination. sNfL values were compared between both groups at the different time points after conversion into Z-scores-adjusted for age and body mass index. RESULTS: Patients with CIDP show elevated sNfL Z-scores (median at baseline: 2.14, IQR: 1.0). There was no significant change in sNfL Z-scores or questionnaire scores within the treatment cycle in either group. There was no significant difference in sNfL levels between the patients with and without symptom fluctuations. CONCLUSIONS: CIDP patients show elevated sNfL levels. However, sNfL is not suitable to reflect patient-reported fluctuations of symptoms. This indicates that symptom fluctuations during treatment with IVIG in patients with CIDP are not caused by a neuroaxonal injury. Furthermore, repeated sNfL measurements within one treatment cycle with IVIG seem to have no benefit for symptom monitoring.

[Over one year of B­cell targeted therapy with Ofatumumab s.c.: first results of a prospective, patient-centered real-world observational study]. / Über ein Jahr B-Zell-gerichtete Therapie mit Ofatumumab s.c.: erste Ergebnisse einer prospektiven, patientenzentrierten Real-world-Beobachtungsstudie.

INTRODUCTION: Ofatumumab (Kesimpta™) is a s.c. applicable anti-CD20 antibody, which has been used in Germany since 2021 for the treatment of relapsing multiple sclerosis (RMS). The self-application offers a high degree of independence from intravenous forms of application with highly effective immunotherapy. In this study we recorded the patient-centered experience in 99 out of 127 patients who were adjusted to the drug by us. The aim was to investigate the tolerability and acceptance from the patient's perspective. METHODS: Data collection was carried out using doctor documentation, questionnaires and telephone interviews. RESULTS: The cohort consists of 127 patients. The patients received 2.8 (± SD 1.7) pre-therapies. The mean duration of therapy with Ofatumumab was 9.8 months (± SD 3.5). Structured data were collected from 99 patients. 23% of patients had no side effects during initial application. 19% rated the side effects as "very mild" and 18% as "mild". In addition to chills/fever (48%), headache (46%), limb pain (45%) and "other symptoms" (19%) also occurred. For subsequent injections, 72% of patients reported no side effects. 87% of patients found handling the medication "very easy". There was one relapse event during therapy. CONCLUSION: Our study shows that Ofatumumab is well accepted and tolerated by patients. There was one relapse event during the observation period. The side effects are mild and occur during initial application. No increased tendency to infection could be observed. The data suggest that Ofatumumab is also an effective and safe treatment option for patients with relapsing remitting multiple sclerosis in real-world use.

In Vitro Myelination of Peripheral Axons in a Coculture of Rat Dorsal Root Ganglion Explants and Schwann Cells.

The process of myelination is essential to enable rapid and sufficient signal transduction in the nervous system. In the peripheral nervous system, neurons and Schwann cells engage in a complex interaction to control the myelination of axons. Disturbances of this interaction and breakdown of the myelin sheath are hallmarks of inflammatory neuropathies and occur secondarily in neurodegenerative disorders. Here, we present a coculture model of dorsal root ganglion explants and Schwann cells, which develops a robust myelination of peripheral axons to investigate the process of myelination in the peripheral nervous system, study axon-Schwann cell interactions, and evaluate the potential effects of therapeutic agents on each cell type separately. Methodologically, dorsal root ganglions of embryonic rats (E13.5) were harvested, dissociated from their surrounding tissue, and cultured as whole explants for 3 days. Schwann cells were isolated from 3-week-old adult rats, and sciatic nerves were enzymatically digested. The resulting Schwann cells were purified by magnetic-activated cell sorting and cultured under neuregulin and forskolin-enriched conditions. After 3 days of dorsal root ganglion explant culture, 30,000 Schwann cells were added to one dorsal root ganglion explant in a medium containing ascorbic acid. The first signs of myelination were detected on day 10 of coculture, through scattered signals for myelin basic protein in immunocytochemical staining. From day 14 onward, myelin sheaths were formed and propagated along the axons. Myelination can be quantified by myelin basic protein staining as a ratio of the myelination area and axon area, to account for the differences in axonal density. This model provides experimental opportunities to study various aspects of peripheral myelination in vitro, which is crucial for understanding the pathology of and possible treatment opportunities for demyelination and neurodegeneration in inflammatory and neurodegenerative diseases of the peripheral nervous system.

Propionate exerts neuroprotective and neuroregenerative effects in the peripheral nervous system.

In inflammatory neuropathies, oxidative stress results in neuronal and Schwann cell (SC) death promoting early neurodegeneration and clinical disability. Treatment with the short-chain fatty acid propionate showed a significant immunoregulatory and neuroprotective effect in multiple sclerosis patients. Similar effects have been described for patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Therefore, Schwann cell's survival and dorsal root ganglia (DRG) outgrowth were evaluated in vitro after propionate treatment and application of H2O2 or S-nitroso-N-acetyl-D-L-penicillamine (SNAP) to evaluate neuroprotection. In addition, DRG resistance was evaluated by the application of oxidative stress by SNAP ex vivo after in vivo propionate treatment. Propionate treatment secondary to SNAP application on DRG served as a neuroregeneration model. Histone acetylation as well as expression of the free fatty acid receptor (FFAR) 2 and 3, histone deacetylases, neuroregeneration markers, and antioxidative mediators were investigated. ß-hydroxybutyrate was used as a second FFAR3 ligand, and pertussis toxin was used as an FFAR3 antagonist. FFAR3, but not FFAR2, expression was evident on SC and DRG. Propionate-mediated activation of FFAR3 and histone 3 hyperacetylation resulted in increased catalase expression and increased resistance to oxidative stress. In addition, propionate treatment resulted in enhanced neuroregeneration with concomitant growth-associated protein 43 expression. We were able to demonstrate an antioxidative and neuroregenerative effect of propionate on SC and DRG mediated by FFAR3-induced histone acetylases expression. Our results describe a pathway to achieve neuroprotection/neuroregeneration relevant for patients with immune-mediated neuropathies.

The impact of the SARS-CoV-2-pandemic on patients with chronic inflammatory neuropathies: results from the German INHIBIT register.

INTRODUCTION: SARS-CoV-2 pandemic is especially compromising for patients with autoimmune diseases with or without immunomodulatory treatment. This study aimed to investigate the longitudinal changes in the health care of patients with immune-mediated neuropathies during the COVID-19 pandemic. METHODS: We performed a longitudinal study using questionnaires in a prospective cohort of patients with immune-mediated neuropathies at two timepoints of the pandemic: May-July 2021 and May-July 2022. RESULTS: The cohort consisted of 73 patients (55 male), mean age 62 years, 68 patients with CIDP, 5 with other immune neuropathies. In 2021, 19.2% of the patients reported a reduced number of physician-patient-contacts, while 13.7% reported this in 2022. Nevertheless, the overall health-care situation worsened from 2021 to 2022: 15.1% reported reduced overall healthcare in 2021, 26.0% in 2022. In 2021, 29.4% of patients reported absence of physio-/occupational therapy, while 34.4% reported this in 2022. Switching immunomodulatory treatment and stretching of treatment intervals occurred more often in 2022 (38.4%) than in 2021 (27.4%). 12 COVID-19-infections occurred overall, with typical only mild symptoms. The rate of fully vaccinated patients was 61.6% and 98.6% in May-July 2021 and 2022, respectively. Only minor side-effects after vaccination were reported. CONCLUSION: Despite mitigation of COVID-19 restrictions from 2021 to 2022, the health-care situation of patients worsened in this time. Reasons could be the international shortage of immunoglobulins during the pandemic and reduced physio/ergotherapy due to lingering regulatory restrictions. Vaccination rate was high in our cohort of patients compared to the general German population and CIDP did not seem to be a risk factor for severe SARS-CoV-2 infections.

Dose-dependent immunomodulatory effects of bortezomib in experimental autoimmune neuritis.

Proteasome inhibition with bortezomib has been reported to exert an immunomodulatory action in chronic autoimmune neuropathies. However, bortezomib used for the treatment of multiple myeloma induces a painful toxic polyneuropathy at a higher concentration. Therefore, we addressed this controversial effect and evaluated the neurotoxic and immunomodulatory mode of action of bortezomib in experimental autoimmune neuritis. Bortezomib-induced neuropathy was investigated in Lewis rats using the von Frey hair test, electrophysiological, qPCR and histological analyses of the sciatic nerve as well as dorsal root ganglia outgrowth studies. The immunomodulatory potential of bortezomib was characterized in Lewis rats after experimental autoimmune neuritis induction with P253-78 peptide. Clinical, electrophysiological, histological evaluation, von Frey hair test, flow cytometric and mRNA analyses were used to unravel the underlying mechanisms. We defined the toxic concentration of 0.2 mg/kg bortezomib applied intraperitoneally at Days 0, 4, 8 and 12. This dosage induces a painful toxic neuropathy but preserves axonal regeneration in vitro. Bortezomib at a concentration of 0.05 mg/kg significantly ameliorated experimental autoimmune neuritis symptoms, improved experimental autoimmune neuritis-induced hyperalgesia and nerve conduction studies, and reduced immune cell infiltration. Furthermore, proteasome inhibition induced a transcriptional downregulation of Nfkb in the sciatic nerve, while its inhibitor Ikba (also known as Nfkbia) was upregulated. Histological analyses of bone marrow tissue revealed a compensatory increase of CD138+ plasma cells. Our data suggest that low dose bortezomib (0.05 mg/kg intraperitoneally) has an immunomodulatory effect in the context of experimental autoimmune neuritis through proteasome inhibition and downregulation of nuclear factor 'kappa-light-chain-enhancer' of activated B-cells (NFKB). Higher bortezomib concentrations (0.2 mg/kg intraperitoneally) induce sensory neuropathy; however, the regeneration potential remains unaffected. Our data empathizes that bortezomib may serve as an attractive treatment option for inflammatory neuropathies in lower concentrations.

Comprehensive approaches for diagnosis, monitoring and treatment of chronic inflammatory demyelinating polyneuropathy.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is the most common chronic inflammatory neuropathy. CIDP is diagnosed according to the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) criteria, which combine clinical features with the electrophysiological evidence of demyelination. However, firstly, diagnosis is challenging, as some patients e.g. with severe early axonal damage do not fulfil the criteria. Secondly, objective and reliable tools to monitor the disease course are lacking. Thirdly, about 25% of CIDP patients do not respond to evidence-based first-line therapy. Recognition of these patients is difficult and treatment beyond first-line therapy is based on observational studies and case series only. Individualized immunomodulatory treatment does not exist due to the lack of understanding of essential aspects of the underlying pathophysiology. Novel diagnostic imaging techniques and molecular approaches can help to solve these problems but do not find enough implementation. This review gives a comprehensive overview of novel diagnostic techniques and monitoring approaches for CIDP and how these can lead to individualized treatment and better understanding of pathophysiology.

Immunomodulatory and anti-oxidative effect of the direct TRPV1 receptor agonist capsaicin on Schwann cells.

BACKGROUND: Only few studies describe the impact of nutritive factors on chronic inflammatory demyelinating polyneuropathy (CIDP), an inflammatory disease of the peripheral nervous system. The active component of chili pepper, capsaicin, is the direct agonist of the transient receptor potential channel vanilloid subfamily member 1. Its anti-inflammatory effect in the animal model experimental autoimmune neuritis (EAN) has been previously demonstrated. METHODS: In the present study, we describe the anti-inflammatory and anti-oxidative influence of capsaicin on Schwann cells (SCs) in an in vitro setting. Hereby, we analyze the effect of capsaicin on Schwann cells' gene expression pattern, major histocompatibility complex class II (MHC-II) presentation, and H2O2-induced oxidative stress. Furthermore, the effect of capsaicin on myelination was examined in a SC-dorsal root ganglia (DRG) coculture by myelin basic protein staining. Finally, in order to investigate the isolated effect of capsaicin on SCs in EAN pathology, we transplant naïve and capsaicin pre-treated SCs intrathecally in EAN immunized rats and analyzed clinical presentation, electrophysiological parameters, and cytokine expression in the sciatic nerve. RESULTS: In SC monoculture, incubation with capsaicin significantly reduces interferon gamma-induced MHC-II production as well as toll-like receptor 4 and intercellular adhesion molecule 1 mRNA expression. Calcitonin gene-related peptide mRNA production is significantly upregulated after capsaicin treatment. Capsaicin reduces H2O2-induced oxidative stress in SC in a preventive, but not therapeutic setting. In a SC-DRG coculture, capsaicin does not affect myelination rate. After intrathecal transplantation of naïve and capsaicin pre-treated SCs in EAN-immunized rats, naïve, but not capsaicin pre-treated intrathecal SCs, ameliorated EAN pathology in rats. CONCLUSIONS: In conclusion, we were able to demonstrate a direct immunomodulatory and anti-oxidative effect of capsaicin in a SC culture by reduced antigen presentation and expression of an anti-inflammatory profile. Furthermore, capsaicin increases the resistance of SCs against oxidative stress. A primary effect of capsaicin on myelination was not proven. These results are in concordance with previous data showing an anti-inflammatory effect of capsaicin, which might be highly relevant for CIDP patients.

Longitudinal study on nerve ultrasound and corneal confocal microscopy in NF155 paranodopathy.

We report the case of a 27-year-old patient with subacute anti-neurofascin-155 neuropathy with bifacial palsy, who showed excellent response to rituximab. We provide longitudinal data of established clinical scores, nerve conduction studies, antibody titers, and novel imaging methods (nerve ultrasonography and corneal confocal microscopy). Clinical and electrophysiological improvement followed the reduction of serum antibody titer and correlated with a reduction of corneal inflammatory cellular infiltrates whereas the increase in the cross-sectional area of the peripheral nerves remained 12 months after first manifestation. Our findings suggest that novel techniques provide useful follow-up parameters in paranodopathies.

Induction of Regulatory Properties in the Intestinal Immune System by Dimethyl Fumarate in Lewis Rat Experimental Autoimmune Neuritis.

Objective: Dimethyl fumarate (DMF) exerts immunomodulatory and neuroprotective effects in the animal model of experimental autoimmune neuritis (EAN) in the Lewis rat. DMF has been shown to modulate gut microbiota in veterinary medicine, however the effects of oral DMF on the gut-associated lymphoid tissue (GALT) remain unknown. Methods: Lewis rats were treated orally twice daily with DMF up to day 10 after immunization with immunogenic P2 peptide. Histological, flow cytometric and RT-PCR analyses of the GALT (intraepithelial layer, lamina propria, and Peyer patches) in duodenum, jejunum, and ileum were performed ex vivo. Moreover, cell transfer experiments were used to examine the protective effects of GALT regulatory T cells of the Peyer patches. Results: In the upper layers of duodenum, DMF induced a reduction of the toll-like receptor 4 (TLR4) mRNA expression. This was combined by a decrease of the pro-inflammatory lamina propria IFN-γ mRNA expression. In the ileum, we detected an immunoregulatory phenotype characterized by an increase of FoxP3 mRNA expression and of the nuclear factor (erythroid-derived-2)- like 2 (Nrf2) downstream molecule heme oxygenase-1 (HO-1) mRNA. Finally, CD4+ CD25+ regulatory T cells were increased in the Peyer patches. In vivo, the protective effect of these regulatory cells was verified by cell transfer into recipient EAN rats. Conclusions: Our results identified a novel immunomodulatory effect of DMF through the different regions and layers of the small intestine, which led to an increase of regulatory T cells, exerting a protective role in experimental neuritis.

Intrathecal triamcinolone acetonide exerts anti-inflammatory effects on Lewis rat experimental autoimmune neuritis and direct anti-oxidative effects on Schwann cells.

BACKGROUND: Corticosteroids dominate in the treatment of chronic autoimmune neuropathies although long-term use is characterized by devastating side effects. METHODS: We introduce the intrathecal application of the synthetic steroid triamcinolone (TRIAM) as a novel therapeutic option in experimental autoimmune neuritis in Lewis rats RESULTS: After immunization with neuritogenic P2 peptide, we show a dose-dependent therapeutic effect of one intrathecal injection of 0.3 or 0.6 mg/kg TRIAM on clinical and electrophysiological parameters of neuritis with a lower degree of inflammatory infiltrates (T cells and macrophages) and demyelination in the sciatic nerve. In vitro studies in Schwann cell cultures showed an increased expression of IL-1 receptor antagonist and reduced expression of Toll-like receptor 4 after incubation with TRIAM as well as a protective effect of TRIAM against oxidative stress after H2O2 exposure. CONCLUSION: Intrathecal TRIAM application could be a novel immunomodulatory and potentially neuroprotective option for autoimmune neuropathies with a direct effect on Schwann cells.

Capsaicin-enriched diet ameliorates autoimmune neuritis in rats.

BACKGROUND: Autoimmune neuropathies are common PNS disorders and effective treatment is challenging. Environmental influence and dietary components are known to affect the course of autoimmune diseases. Capsaicin as pungent component of chili-peppers is common in human nutrition. An influence of capsaicin on autoimmune diseases has been postulated. METHODS: We tested capsaicin in the animal model of experimental autoimmune neuritis (EAN) in Lewis rat. Rats were immunized with P2-peptide and were treated with capsaicin in different preventive settings. Electrophysiological, histological, and molecular biological analyses of the sciatic nerve were performed to analyze T-cell and macrophage cell count, TRPV1, and cytokine expression. Moreover, FACS analyses including the intestinal immune system were executed. RESULTS: We observed an immunomodulatory effect of an early preventive diet-concept, where a physiological dosage of oral capsaicin was given 10 days before immunization in EAN. A reduced inflammation of the sciatic nerve was significant detectable clinically, electrophysiologically (CMAPs reduced in control group p < 0.01; increase of nerve conduction blocks in control group p < 0.05), histologically (significant reduction of T-cells, macrophages and demyelination), and at cytokine level. In contrast, this therapeutic effect was missing with capsaicin given from the day of immunization onwards. As possible underlying mechanism, we were able to show changes in the expression of the capsaicin receptor in the sciatic nerve and the small intestine, as well as altered immune cell populations in the small intestine. CONCLUSION: This is the first report about the immunomodulatory effect of the common nutrient, capsaicin, in an experimental model for autoimmune neuropathies.