Immunologische Charakterisierung von Patienten mit Chronisch Inflammatorisch Demyelinisierender Polyneuropathie (CIDP) und ihren Varianten

Bislang sind die zugrundeliegende Pathomechanismen bei der CIDP wenig verstanden. In den vorgestellten Studien wurden mehrere Kandidatenantigene bei Patienten mit CIDP untersucht, die sowohl dem peripheren Myelin als auch der para- sowie nodalen Region eines Nerven entstammen. Es konnte mit Hilfe des Elispot-Assays gezeigt werden, dass CIDP-Patienten autoreaktive T-Zellantworten sowohl gegenüber peripher Myelin-spezifischen- als auch (para)nodalen Antigenen aufweisen. Dabei fanden sich in der Gruppe der atypischen CIDP insgesamt mehr autoreaktive T-Zell-Responsen verbunden mit erhöhten Frequenzen an T-Effektor-Memory-Zellen. In einer Subgruppenanalyse, in denen verschiedene periphere Myelinantigene als auch Antigene gegen die para- und nodale Nervenregion getestet wurden, zeigten sich Unterschiede in den einzelnen klinischen Subgruppen und der klassischen CIDP. Dabei zeigten Patienten mit sensibler und klassischer CIDP sowie MADSAM-Patienten die jeweils breiteteste Autoimmunantwort gegenüber den getesteten Antigenen. Der Nachweis von Immunantworten gegenüber mindestens 2 der getesteten Antigene war prädiktiv für das Vorhandensein einer CIDP. In der ROC-Analyse zeigte sich eine gute Trennschärfe für das Vorhandensein einer MADSAM (NF186-Antwort) bzw. einer sensiblen CIDP (MBP und P0-Antwort). Autoreaktive T-Zell-Antworten gegenüber peripheren Myelinantigenen waren vor allem in den Patienten in größerer Frequenz nachweisbar, die gut auf eine immunmodulatorische Therapie ansprachen und sanken im Langzeitverlauf unter der Therapie mit IVIGs. Diese Myelin-spezifischen T-Zell-Antworten gingen mit einem veränderten T-Zell-Gedächtniskompartiment einher, welches insbesondere durch eine Reduktion von CD8+Effektor–Memory-Zellen gekennzeichnet war. Interessanterweise zeigten sich Unterschiede im Gedächtniszell-Kompartiment in der Subgruppenanalyse zwischen IVIG- und GS Langzeit-behandelten Patienten. Während Cortison-behandelte Patienten eine Reduktion durchweg aller CD4+ und tendenziell CD8+Subpopulationen aufwiesen, zeigten die IVIG-behandelten Langzeittherapie-Patienten eine spezifische Veränderung nur des CD8-Effektor-Kompartiments. Neben den T-Zell-Antworten waren in CIDP-Patienten auch Gangliosid-Antikörper, insbesondere GM1, aSF und GD1b-IgM, mittels der neuen Methode des Line Immunoassays nachweisbar. Diese fanden sich vor allem in der Gruppe der nach EFNS-Kriterien sicheren CIDP/MMN und in Assoziation mit Leitungsblöcken und motorischen Ausfällen. Im Gegensatz zu früheren Arbeiten zeigten sich in der hier vorgestellten Arbeit insgesamt höhere Prävalenzen dieser Antikörper von IgM-Typ, was auf eine sekundäre Antikörper-Antwort basierend auf eine prädominierende T-Zell vermittelte Demyelinisierung hindeuten könnte. Zusammenfassend erscheinen die vorgestellten Daten hinsichtlich autoantigen-spezifischer T-Zellantworten und Gangliosid-Antikörper ein vielversprechender Biomarker-Ansatz. Vor dem Hintergrund der Seltenheit der Erkrankung sind größer angelegte Studien vonnöten. Schwerpunkt dieser größer angelegter Kohortenstudien sollte daher die Validierung dieser Biomarker sein, um perspektivisch ihren Einsatz als diagnostische und prognostische Marker bei der CIDP und ihren Varianten zu ermöglichen

Neurofascin (NF) 155-and NF186-Specific T Cell Response in a Patient Developing a Central Pontocerebellar Demyelination after 10 Years of CIDP

Background: Information and pathobiological understanding about central demyelinating manifestation in patients, who primarily suffer from chronic inflammatory demyelinating polyneuropathy (CIDP), are scarce. Methods: IFN-gamma-response as well as antibodies against the (para) nodal antigens neurofascin (NF) 155 and NF 186 had been tested by Elispot assay and ELISA before clinical manifestation and at follow-up. Case description and results: The patient described here developed a subacute brainstem syndrome more than 10 years after diagnosis of CIDP under low-dose maintenance treatment of intravenous immunoglobulins (IVIG). MRI revealed enhancing right-sided pontocerebellar lesion. CSF examination showed mild pleocytosis and elevated protein, and negative oligoclonal bands. Further diagnostics exclude differential diagnoses such as tuberculoma, sarcoidosis, or metastasis. Specific IFN-gamma response against NF155 and NF186 as measured by Elispot assay was elevated before clinical manifestation. NF155 and NF186 antibodies were negative. Escalation of IVIG treatment at 2 g/kg BW followed by 1.4 g/kg BW led to clinical remission albeit to a new asymptomatic central lesion. Follow-up NF155 and NF186-Elispot turned negative. Conclusion: The case reported here with a delayed central manifestation after an initially typical CIDP and NF155 and NF186 T cell responses does not resemble described cases of combined central and peripheral demyelination but may reflect a novel subtype within the great clinical heterogeneity of CIDP

Preventive Antibacterial Therapy in Acute Ischemic Stroke: A Randomized Controlled Trial

BACKGROUND: Pneumonia is a major risk factor of death after acute stroke. In a mouse model, preventive antibacterial therapy with moxifloxacin not only prevents the development of post-stroke infections, it also reduces mortality, and improves neurological outcome significantly. In this study we investigate whether this approach is effective in stroke patients. METHODS: Preventive ANtibacterial THERapy in acute Ischemic Stroke (PANTHERIS) is a randomized, double-blind, placebo-controlled trial in 80 patients with severe, non-lacunar, ischemic stroke (NIHSS>11) in the middle cerebral artery (MCA) territory. Patients received either intravenous moxifloxacin (400 mg daily) or placebo for 5 days starting within 36 hours after stroke onset. Primary endpoint was infection within 11 days. Secondary endpoints included neurological outcome, survival, development of stroke-induced immunodepression, and induction of bacterial resistance. FINDINGS: On intention-to treat analysis (79 patients), the infection rate at day 11 in the moxifloxacin treated group was 15.4% compared to 32.5% in the placebo treated group (p = 0.114). On per protocol analysis (n = 66), moxifloxacin significantly reduced infection rate from 41.9% to 17.1% (p = 0.032). Stroke associated infections were associated with a lower survival rate. In this study, neurological outcome and survival were not significantly influenced by treatment with moxifloxacin. Frequency of fluoroquinolone resistance in both treatment groups did not differ. On logistic regression analysis, treatment arm as well as the interaction between treatment arm and monocytic HLA-DR expression (a marker for immunodepression) at day 1 after stroke onset was independently and highly predictive for post-stroke infections. INTERPRETATION: PANTHERIS suggests that preventive administration of moxifloxacin is superior in reducing infections after severe non-lacunar ischemic stroke compared to placebo. In addition, the results emphasize the pivotal role of immunodepression in developing post-stroke infections. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN74386719

Neurofascin and Compact Myelin Antigen-Specific T Cell Response Pattern in Chronic Inflammatory Demyelinating Polyneuropathy Subtypes

ObjectiveThe objective of this study is to investigate whether chronic inflammatory demyelinating polyneuropathy (CIDP) and its subtypes differ in their type 1 T-helper (TH1) cell response against nodal/paranodal neurofascin (NF186, NF155) as well as myelin protein zero (P0 180–199) and myelin basic protein (MBP 82–100).MethodsInterferon-gamma (IFN-γ) enzyme-linked immunospot assay was used to detect antigen-specific T cell responses in 48 patients suffering typical CIDP (n = 18), distal acquired demyelinating polyneuropathy (n = 8), multifocal acquired demyelinating sensory and motor polyneuropathy (MADSAM; n = 9), and sensory CIDP (n = 13) compared to other non-immune polyneuropathy (ON; n = 19) and healthy controls (n = 9).ResultsCompared to controls, MADSAM and sensory CIDP patients showed broadest IFN-γ T cell responses to all four antigens. Positive IFN-γ responses against two or more antigens were highly predictive for CIDP (positive predictive value = 0.95) and were found in 77% of CIDP patients. Patients with limited antigen-specific response were females, more severely affected with neuropathic pain and proximal paresis. The area under the receiver operating characteristics curve (AUC) of NF186 in MADSAM was 0.94 [95% confidential interval (CI) 0.82–1.00] compared to ON. For sensory CIDP, AUC of P0 180–199 was 0.94 (95% CI 0.86–1.00) and for MBP 82–100 0.95 (95% CI 0.88–1.00) compared to ON.ConclusionCell-mediated immune responses to (para)nodal and myelin-derived antigens are common in CIDP. TH1 response against NF186 may be used as a biomarker for MADSAM and TH1 responses against P0 180–199 and MBP 82–100 as biomarkers for sensory CIDP. Larger multicenter studies study are warranted in order to establish these immunological markers as a diagnostic tools

Demographic and clinical characteristics of the patient sample.

<p><i>Note.</i> Groups: SA =  subacute, CH =  chronic, CG =  control group. Pt =  patient; M/F =  male/female. NIHSS: National Institutes of Health Stroke Scale. Stroke etiology: i =  ischemic, h =  hemorrhagic stroke. V&TDS: visual and tactile double stimulation. CAV screen: CAV visual field screening. CAV-ET: CAV extinction test. NET Score: for subtests 1 to 8 and for the whole test battery. Mean (M) and standard deviation (SD) given for patients and healthy controls.</p

Lesion patterns of individual patients.

<p>Patient numbers correspond to patient IDs in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0082892#pone-0082892-t001" target="_blank">Table 1</a> (patients #2-10). No MRI was available for patient #1. Right side of the brain corresponds to right hemisphere.</p

Star Cancellation Test: Percentage of detected stars, split into test-system, experimental group and visual field.

<p>The figure shows means and standard errors. Best possible performance (100%) in NET was 27 stars, in CM 20 stars per side. CM: Circle-Monitor, NET: Neglect-Test.</p

Variables included in the discriminant analysis.

<p><i>Note.</i> CM: Circle Monitor. NET: Neglect Test. Explained variance: explained variance by the given predictors. Stars (*) indicate significant predictors in the discriminant analyses.</p