The Inverse Lhermitte Phenomenon Suggests Nitrous Oxide-Induced Myelopathy: Case Report and Review of the Literature

Nitrous oxide-induced myelopathy is a relatively well-known clinical entity. Less well-known, however, is the rare inverse Lhermitte phenomenon, where neck flexion elicits an ascending, rather than descending, electric shock-like sensation. This is a characteristic symptom and sign that may occur in nitrous oxide toxicity. In this article, we present the case of a patient who was admitted to our hospital with suspected Guillain-Barré syndrome due to her ascending numbness and unsteady gait. We describe her examination and laboratory features leading to the correct diagnosis, along with a historical review of the various subtypes of the Lhermitte phenomenon and the pathophysiology of nitrous oxide-induced myelopathy

Transient Worsening of Optic Neuropathy as a Sequela of the Jarisch-Herxheimer Reaction in the Treatment of Lyme Disease.

A 58-year-old woman developed neurologic and neuroophthalmologic manifestations of Lyme disease, including a radiculomyelitis, cranial neuritis and mild right optic neuropathy. Upon treatment with intravenous ceftriaxone a Jarisch-Herxheimer reaction occurred with encephalopathy, mild fever, worsening radiculomyelitis, and deterioration of her visual acuity. Intravenous methylprednisolone was given, and the visual acuity recovered over 72 hours. This case suggests that transient worsening of optic neuropathy can develop as a sequela of the Jarisch-Herxheimer reaction in the treatment of Lyme disease

Type I and Type II Interferon Coordinately Regulate Suppressive Dendritic Cell Fate and Function during Viral Persistence.

Persistent viral infections are simultaneously associated with chronic inflammation and highly potent immunosuppressive programs mediated by IL-10 and PDL1 that attenuate antiviral T cell responses. Inhibiting these suppressive signals enhances T cell function to control persistent infection; yet, the underlying signals and mechanisms that program immunosuppressive cell fates and functions are not well understood. Herein, we use lymphocytic choriomeningitis virus infection (LCMV) to demonstrate that the induction and functional programming of immunosuppressive dendritic cells (DCs) during viral persistence are separable mechanisms programmed by factors primarily considered pro-inflammatory. IFNγ first induces the de novo development of naive monocytes into DCs with immunosuppressive potential. Type I interferon (IFN-I) then directly targets these newly generated DCs to program their potent T cell immunosuppressive functions while simultaneously inhibiting conventional DCs with T cell stimulating capacity. These mechanisms of monocyte conversion are constant throughout persistent infection, establishing a system to continuously interpret and shape the immunologic environment. MyD88 signaling was required for the differentiation of suppressive DCs, whereas inhibition of stimulatory DCs was dependent on MAVS signaling, demonstrating a bifurcation in the pathogen recognition pathways that promote distinct elements of IFN-I mediated immunosuppression. Further, a similar suppressive DC origin and differentiation was also observed in Mycobacterium tuberculosis infection, HIV infection and cancer. Ultimately, targeting the underlying mechanisms that induce immunosuppression could simultaneously prevent multiple suppressive signals to further restore T cell function and control persistent infections

Type I and Type II Interferon Coordinately Regulate Suppressive Dendritic Cell Fate and Function during Viral Persistence

<div><p>Persistent viral infections are simultaneously associated with chronic inflammation and highly potent immunosuppressive programs mediated by IL-10 and PDL1 that attenuate antiviral T cell responses. Inhibiting these suppressive signals enhances T cell function to control persistent infection; yet, the underlying signals and mechanisms that program immunosuppressive cell fates and functions are not well understood. Herein, we use lymphocytic choriomeningitis virus infection (LCMV) to demonstrate that the induction and functional programming of immunosuppressive dendritic cells (DCs) during viral persistence are separable mechanisms programmed by factors primarily considered pro-inflammatory. IFNγ first induces the <i>de novo</i> development of naive monocytes into DCs with immunosuppressive potential. Type I interferon (IFN-I) then directly targets these newly generated DCs to program their potent T cell immunosuppressive functions while simultaneously inhibiting conventional DCs with T cell stimulating capacity. These mechanisms of monocyte conversion are constant throughout persistent infection, establishing a system to continuously interpret and shape the immunologic environment. MyD88 signaling was required for the differentiation of suppressive DCs, whereas inhibition of stimulatory DCs was dependent on MAVS signaling, demonstrating a bifurcation in the pathogen recognition pathways that promote distinct elements of IFN-I mediated immunosuppression. Further, a similar suppressive DC origin and differentiation was also observed in <i>Mycobacterium tuberculosis</i> infection, HIV infection and cancer. Ultimately, targeting the underlying mechanisms that induce immunosuppression could simultaneously prevent multiple suppressive signals to further restore T cell function and control persistent infections.</p></div

Letters to the editor

SCOPUS: le.jinfo:eu-repo/semantics/publishe

<i>In vivo</i> localization and identification of immunoregulatory DCs during viral persistence.

<p><b>A.</b> Sections from IL-10 reporter mice infected with LCMV-Cl13 for 9 or 36 days were stained for B cells, CD4+ T cells, and CD90.1 (IL-10) and visualized at 10x magnification. <b>B.</b> CD39 and CD95 expression on splenic CD11b+ DCs from naive IL-10 reporter mice or IL-10 reporter mice infected with LCMV-Cl13 for 9 or 30 days and their corresponding expression of CD90.1 (IL-10) and PDL1 within the iregDC (red) and stimDC (blue) populations. Bar graphs indicate the geometric mean fluorescence intensity (MFI) of CD90.1 (IL-10) and PDL1 expression by iregDCs (red) and stimDCs (blue). DC are characterized as being viability dye-, CD45+, Thy1.2-, NK1.1-, Ly6G-, CD11c++ (high), CD11b+. <b>C.</b> The number of iregDCs (red) and stimDCs (blue) based on CD39 and CD95 expression at the indicated time point after LCMV-Cl13 infection. <b>D.</b> Histograms of the indicated protein on iregDCs (red) and stimDCs (blue) at day 9 and day 30 following LCMV-Cl13 infection. <b>E.</b> iregDCs and stimDCs were sorted from splenocytes at day 9 of LCMV-Cl13 infection and cultured with LCMV specific CD4+ T cells (SMARTA) for 3 days with IL-10R blocking antibody, PDL1 blocking antibody, or media alone. Bar graph represents the proportion of proliferated SMARTA cells after the culture. Data in 1E show a single experiment using iregDC and stimDC sorted from a pool of 8 mice in order to obtain adequate numbers of each population. Data are representative of 2 or more independent experiments each consisting of 3–4 mice per group. *, p<0.05.</p

Monocyte-derived iregDCs develop in <i>Mtb</i> infection, HIV infection and cancer.

<p><b>A.</b> Flow plots show CD39 and PDL1 expression on splenic CD11b+ DCs from IL-10 reporter mice either uninfected or infected with virulent <i>Mtb</i> for 36 days. Histograms indicate expression of the indicated protein on iregDC (red) and stimDC (blue). Bar graphs indicate the number of iregDC and stimDC in uninfected and <i>Mtb</i> infected mice. <b>B.</b> Flow plots show CD39, PDL1 and monocyte-associated proteins on CD11c++, HLA-DR+, CD14+ iregDC (red) and stimDC (blue) from the peripheral blood of naïve humanized mice and HIV infected humanized mice. <b>C.</b> Flow plots show CD39, PDL1 and monocyte-associated proteins on CD11b+, CD11c++ iregDC (red) and stimDC (blue) on B16 melanoma infiltrating leukocytes. Data are representative of 2 or more independent experiments each consisting of 4–7 mice per group. *, p<0.05.</p

iregDCs have a distinct expression profile compared to stimDCs.

<p>StimDCs and iregDCs were obtained from day 9 LCMV-Cl13 infected mouse splenocytes, RNA was harvested and subjected to RNA-seq. <b>A.</b> Graph scatter shows the log-transformed expression values for genes expressed at 2 RPKM or more in at least one sample. Dots are color-coded based on the ratio of RPKM values to indicate differentially expressed (DE) genes between the two cell types. The number of genes in each DE group are indicated in the top left (higher in stimDCs) and bottom right (higher in iregDCs) corners. Selected DE genes from this dataset are shown in the rest of the panels to highlight important gene groups as indicated on top of each panel. <b>B.</b> Gene Ontology (GO) term over representation analysis was performed on a set of genes that were at least 5-fold differentially expressed between the iregDC and stimDC samples. Plots show the statistical significance of GO terms that are enriched in genes expressed at higher levels in iregDCs and stimDCs. The number of genes that were classified under a particular GO term are indicated in brackets. GO terms with an adjusted (Benjamini-Hochberg method) p-value of < = 0.05 were considered to be enriched in the DE gene set. <b>C.</b> Bar graphs show the fold change in the indicated gene. Up on the y-axis indicates increase in iregDC (red). Down on the y-axis indicates increase in stimDC (green). The number in parenthesis indicates the RPKM value of the highest sample (to indicate relative expression level).</p