interleukin-8 and Neuromyelitis-Optica

The changes in the serum levels of aquaporin-4-IgG (AQP4-IgG), immunoglobulins, and inflammatory mediators in neuromyelitis optica spectrum disorder (NMOSD) cases treated with immunoadsorption have been rarely described in detail. Here we report a 29-year-old steroid-resistant NMOSD female with a severe disability (bilateral blindness and paraplegia) who received protein-A immunoadsorption as a rescue treatment. During the total 5 sessions, the circulating level of AQP4-IgG, immunoglobulins, and complement proteins (C3 and C4) showed a rapid and sawtooth-like decrease, and the serum AQP4-IgG titer declined from 1:320 to below the detectable limit at the end of the 3rd procedure. Of all the antibodies, IgG had the biggest removal rate (>96.1%), followed by IgM (>66.7%) and IgA (53%), while complement C3 and C4 also dropped by 73% and 65%, respectively. The reduced pro-inflammatory cytokines (interleukin-8 and tumor necrosis factor-α) and marked increased lymphocyte (T and B cell) counts were also observed. The improvement of symptoms initiated after the last session, with a low AQP4-IgG titer (1:32) persisting thereafter. Accordingly, protein-A immunoadsorption treatment could be one of the potential rescue therapies for steroid-resistant NMOSD patients with a severe disability.

Topics: Adult; Aquaporin 4; Biomarkers; Complement C3; Complement C4; Female; Humans; Immunoglobulin G; Interleukin-8; Lymphocyte Count; Neuromyelitis Optica; Plasmapheresis; Staphylococcal Protein A; Tumor Necrosis Factor-alpha

Repulsive guidance molecule-a (RGMa) is a glycosylphosphatidylinositol-linked glycoprotein which has multiple functions including axon growth inhibition and immune regulation. However, its role in the pathophysiology of neuromyelitis optica (NMO) is poorly understood. Perivascular astrocytopathy, which is induced by the leakage of aquaporin-4 (AQP4)-specific IgG into the central nervous system parenchyma, is a key feature of NMO pathology. We investigated the RGMa involvement in the pathology of NMO astrocytopathy, and tested a therapeutic potential of humanized anti-RGMa monoclonal antibody (RGMa-mAb).. Using a clinically relevant NMO rat model, we evaluated the therapeutic effect of a RGMa-mAb by behavioral testing, immunohistochemistry, and gene expression assay. We further performed in vitro experiments to address the RGMa-signaling in macrophages.. In both NMO rats and an NMO-autopsied sample, RGMa was expressed by the spared neurons and astrocytes, whereas its receptor neogenin was expressed by infiltrating macrophages. AQP4-IgG-induced astrocytopathy and clinical exacerbation in NMO rats were ameliorated by RGMa-mAb treatment. RGMa-mAb treatment significantly suppressed neutrophil infiltration, and decreased the expression of neutrophil chemoattractants. Interestingly, neogenin-expressing macrophages accumulated in the lesion expressed CXCL2, a strong neutrophil chemoattractant, and further analysis revealed that RGMa directly regulated CXCL2 expression in macrophages. Finally, we found that our NMO rats developed neuropathic pain, and RGMa-mAb treatment effectively ameliorated the severity of neuropathic pain.. RGMa signaling in infiltrated macrophages is a critical driver of neutrophil-related astrocytopathy in NMO lesions, and RGMa-mAb may provide an efficient therapeutic strategy for NMO-associated neuropathic pain and motor deficits in patients with NMO. ANN NEUROL 2022;91:532-547.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Aquaporin 4; GPI-Linked Proteins; Humans; Immunoglobulin G; Interleukin-8; Macrophages; Membrane Proteins; Nerve Tissue Proteins; Neuralgia; Neuromyelitis Optica; Neutrophils; Rats

In neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), neutrophils are found in CNS lesions. We previously demonstrated that NMOSD neutrophils show functional deficiencies. Thus, we hypothesized that neutrophil accumulation in the CNS may be facilitated by impairments affecting mechanisms of neutrophil death.. To evaluate cell death in blood neutrophils from aquaporin-4 (AQP4)-IgG-seropositive NMOSD and MOGAD patients as well as matched healthy controls (HC) using in vitro assays.. Twenty-eight AQP4 + NMOSD and 19 MOGAD patients in stable disease phase as well as 45 age- and sex-matched HC were prospectively recruited. To induce cell death, isolated neutrophils were cultured with/without phorbol 12-myristate 13-acetate (PMA). Spontaneous and PMA-induced NETosis and apoptosis were analyzed using 7-AAD and annexin-V by flow cytometry. Caspase-3 was assessed by western blot. Myeloperoxidase-DNA complexes (MPO-DNA), MPO and elastase were evaluated by ELISA, and cell-free DNA (cfDNA) by a fluorescence-based assay. Reactive oxygen species (ROS) were evaluated by a dihydrorhodamine 123-based cytometric assay. Serum GM-CSF, IL-6, IL-8, IL-15, TNF-ɑ and IL-10 were evaluated by multiplex assays, and neurofilament light chain (NfL) by single-molecule array assay.. In response to PMA, neutrophils from AQP4 + NMOSD but not from MOGAD patients showed an increased survival, and subsequent reduced cell death (29.6% annexin V. AQP4 + NMOSD neutrophils showed an increased survival capacity in response to PMA when compared to matched HC neutrophils. Although the data indicate that the apoptotic but not the NETotic response is altered in these neutrophils, additional evaluations are required to validate this observation.

Topics: Acetates; Annexin A5; Aquaporin 4; Autoantibodies; Caspase 3; Cell Death; Cell-Free Nucleic Acids; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunoglobulin G; Interleukin-10; Interleukin-15; Interleukin-6; Interleukin-8; Myelin-Oligodendrocyte Glycoprotein; Myristates; Neuromyelitis Optica; Neutrophils; Pancreatic Elastase; Peroxidase; Phorbols; Reactive Oxygen Species; Tumor Necrosis Factor-alpha

There are two distinct subtypes of multiple sclerosis in Asians, opticospinal (OS-multiple sclerosis) and conventional (C-multiple sclerosis). In OS-multiple sclerosis, selective and severe involvement of the optic nerves and spinal cord is characteristic, though its mechanisms are unknown. The present study aimed to find out possible differences in the cytokine/chemokine profiles in CSF between OS-multiple sclerosis and C-multiple sclerosis and to delineate the relationships between these profiles and neuroimaging and pathological features. Sixteen cytokines/chemokines, namely interleukin (IL)-1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p70), IL-13, IL-17, interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha, granulocyte colony-stimulating factor (G-CSF), monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1beta (MIP-1beta), were measured simultaneously in CSF supernatants from 40 patients with relapsing-remitting multiple sclerosis (20 OS-multiple sclerosis and 20 C-multiple sclerosis) at relapse and 19 control patients with spinocerebellar degeneration (SCD), together with intracellular production of IFN-gamma and IL-4 in CSF CD4+ T cells. In CSF supernatants relative to controls, IL-17, MIP-1beta, IL-1beta and IL-13 were only significantly increased in OS-multiple sclerosis patients, while TNF-alpha was only significantly increased in C-multiple sclerosis patients, using a cut-off level of 1 pg/ml. IL-8 was significantly elevated in both OS-multiple sclerosis and C-multiple sclerosis patients. MCP-1 was significantly decreased in both OS-multiple sclerosis and C-multiple sclerosis patients, while IL-7 was only significantly decreased in C-multiple sclerosis patients. IL-17, IL-8 and IL-5 were significantly higher in OS-multiple sclerosis patients than in C-multiple sclerosis patients. The increases in IL-17 and IL-8 in OS-multiple sclerosis were still significant even after exclusion of the patients undergoing various immunomodulatory therapies. Assays of intracellular cytokine production revealed that both the IFN-gamma+IL-4- T-cell percentage and intracellular IFN-gamma/IL-4 ratio in CSF cells were significantly greater in C-multiple sclerosis patients than in controls. Contrarily, OS-multiple sclerosis patients showed not only a significantly greater percentage of IFN-gamma+IL-4- T cells than controls but also a significantly higher percentage of IFN-gamma-IL-4+ T cells than C-multiple sclerosis patient

Topics: Adult; Aged; Aged, 80 and over; CD4-Positive T-Lymphocytes; Chemokines; Cytokines; Female; Humans; Interleukin-17; Interleukin-8; Magnetic Resonance Imaging; Male; Middle Aged; Neuromyelitis Optica; Neutrophil Infiltration; Spinal Cord