RESUMEN
Background: Patients suffering from neurological symptoms after COVID-19 vaccination (post-COVID-19 vaccination syndrome (PCVS)) have imposed an increasing challenge on medical practice, as diagnostic precision and therapeutic options are lacking. Underlying autoimmune dysfunctions, including autoantibodies, have been discussed in neurological disorders after SARS-CoV-2 infection and vaccination. Here, we describe the frequency and targets of autoantibodies against peripheral nervous system tissues in PCVS. Methods: Sera from 50 PCVS patients with peripheral neurological symptoms after COVID-19 vaccination and 35 vaccinated healthy controls were used in this study. IgG autoreactivity was measured via indirect immunofluorescence assays on mouse sciatic nerve teased fibers. The frequencies of autoantibodies were compared between groups using Fisher's exact test. Serum anti-ganglioside antibodies were measured in ganglioside blots. Autoantibody target identification was performed using immunoprecipitation coupled to mass spectrometry. Subsequent target confirmation was conducted via cell-based assays and ELISA. Results: Compared with controls, PCVS patients had a significantly greater frequency of autoantibodies against peripheral nervous system structures (9/50(18%) vs 1/35(3%); p=0.04). Autoantibodies bound to paranodes (n=5), axons (n=4), Schmidt-Lanterman incisures (n=2) and Schwann cell nuclei (n=1). Conversely, antibodies against gangliosides were absent in PCVS patients. Target identification and subsequent confirmation revealed various subunits of neurofilaments as well as DFS-70 as autoantibody epitopes. Conclusion: Our data suggest that autoantibodies against nervous system tissue could be relevant in PCVS patients. Autoantibodies against neurofilaments and cell nuclei with so far non-established links to this disease spectrum should be further elucidated to determine their biomarker potential.
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Autoanticuerpos , Vacunas contra la COVID-19 , COVID-19 , Inmunoglobulina G , SARS-CoV-2 , Humanos , Autoanticuerpos/inmunología , Autoanticuerpos/sangre , Masculino , Femenino , Inmunoglobulina G/inmunología , Inmunoglobulina G/sangre , Persona de Mediana Edad , COVID-19/inmunología , SARS-CoV-2/inmunología , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , Anciano , Ratones , Animales , Adulto , Vacunación , Gangliósidos/inmunología , Nervios Periféricos/inmunologíaRESUMEN
INTRODUCTION/AIMS: The precise relationship between molecular mimicry and tissue-specific autoimmunity is unknown. Major histocompatibility complex (MHC) class II antigen presenting cell-CD4+ T-cell receptor complex interactions are necessary for adaptive immunity. This study aimed to determine the role of endoneurial endothelial cell MHC class II in autoimmune polyneuropathy. METHODS: Cryopreserved Guillain-Barré syndrome (GBS) patient sural nerve biopsies and sciatic nerves from the severe murine experimental autoimmune neuritis (sm-EAN) GBS model were studied. Cultured conditional ready MHC Class II antigen A-alpha chain (H2-Aa) embryonic stem cells were used to generate H2-Aaflox/+ C57BL/6 mice. Mice were backcrossed and intercrossed to the SJL background to generate H2-Aaflox/flox SJL mice, bred with hemizygous Tamoxifen-inducible von Willebrand factor Cre recombinase (vWF-iCre/+) SJL mice to generate H2-Aaflox/flox; vWF-iCre/+ mice to study microvascular endothelial cell adaptive immune responses. Sm-EAN was induced in Tamoxifen-treated H2-Aaflox/flox; vWF-iCre/+, H2-Aaflox/flox; +/+, H2-Aa+/+; vWF-iCre/+ and untreated H2-Aaflox/flox; vWF-iCre/+ adult female SJL mice. Neurobehavioral, electrophysiological and histopathological assessments were performed at predefined time points. RESULTS: Endoneurial endothelial cell MHC class II expression was observed in normal and inflamed human and mouse peripheral nerves. Tamoxifen-treated H2-Aaflox/flox; vWF-iCre/+ mice were resistant to sm-EAN despite extensive MHC class II expression in lymphoid and non-lymphoid tissues. DISCUSSION: A conditional MHC class II knockout mouse to study cell- and time-dependent adaptive immune responses in vivo was developed. Initial studies show microvascular endothelial cell MHC class II expression is necessary for peripheral nerve specific autoimmunity, as advocated by human in vitro adaptive immunity and ex vivo transplant rejection studies.
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Inmunidad Adaptativa , Antígenos de Histocompatibilidad Clase II , Ratones Endogámicos C57BL , Ratones Noqueados , Animales , Ratones , Antígenos de Histocompatibilidad Clase II/metabolismo , Antígenos de Histocompatibilidad Clase II/genética , Humanos , Síndrome de Guillain-Barré/inmunología , Síndrome de Guillain-Barré/genética , Síndrome de Guillain-Barré/patología , Neuritis Autoinmune Experimental/inmunología , Neuritis Autoinmune Experimental/patología , Neuritis Autoinmune Experimental/genética , Nervio Ciático/inmunología , Nervio Ciático/metabolismo , Nervio Ciático/patología , Nervios Periféricos/inmunología , Nervios Periféricos/metabolismo , Nervios Periféricos/patología , Femenino , Células Endoteliales/inmunología , Células Endoteliales/metabolismo , Nervio Sural/patología , Nervio Sural/inmunología , Masculino , Factores de TiempoRESUMEN
Guillain-Barré syndrome (GBS) is a rare heterogenous disorder of the peripheral nervous system, which is usually triggered by a preceding infection, and causes a potentially life-threatening progressive muscle weakness1. Although GBS is considered an autoimmune disease, the mechanisms that underlie its distinct clinical subtypes remain largely unknown. Here, by combining in vitro T cell screening, single-cell RNA sequencing and T cell receptor (TCR) sequencing, we identify autoreactive memory CD4+ cells, that show a cytotoxic T helper 1 (TH1)-like phenotype, and rare CD8+ T cells that target myelin antigens of the peripheral nerves in patients with the demyelinating disease variant. We characterized more than 1,000 autoreactive single T cell clones, which revealed a polyclonal TCR repertoire, short CDR3ß lengths, preferential HLA-DR restrictions and recognition of immunodominant epitopes. We found that autoreactive TCRß clonotypes were expanded in the blood of the same patient at distinct disease stages and, notably, that they were shared in the blood and the cerebrospinal fluid across different patients with GBS, but not in control individuals. Finally, we identified myelin-reactive T cells in the nerve biopsy from one patient, which indicates that these cells contribute directly to disease pathophysiology. Collectively, our data provide clear evidence of autoreactive T cell immunity in a subset of patients with GBS, and open new perspectives in the field of inflammatory peripheral neuropathies, with potential impact for biomedical applications.
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Autoinmunidad , Linfocitos T CD8-positivos , Síndrome de Guillain-Barré , Nervios Periféricos , Enfermedades del Sistema Nervioso Periférico , Células TH1 , Humanos , Biopsia , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Síndrome de Guillain-Barré/sangre , Síndrome de Guillain-Barré/líquido cefalorraquídeo , Síndrome de Guillain-Barré/etiología , Síndrome de Guillain-Barré/inmunología , Antígenos HLA-DR/inmunología , Epítopos Inmunodominantes/inmunología , Vaina de Mielina/inmunología , Nervios Periféricos/inmunología , Nervios Periféricos/patología , Enfermedades del Sistema Nervioso Periférico/complicaciones , Enfermedades del Sistema Nervioso Periférico/inmunología , Enfermedades del Sistema Nervioso Periférico/patología , Receptores de Antígenos de Linfocitos T/inmunología , Células TH1/inmunología , Células TH1/patología , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/patología , Memoria InmunológicaRESUMEN
Pruritus is a skin-specific sensation that is observed in various skin diseases, especially in inflammatory skin diseases such as atopic dermatitis, and is deeply involved in their pathogenesis. Pruritus also adversely affects patients' sleep and mental health, placing a heavy burden on daily life. As such, pruritus control is important to the maintenance of health. The mechanism of pruritus has recently been clarified and the discovery of various pruritus mediators, the identification of specific nerves that transmit pruritus and the accumulation of knowledge on pruritus perception have led to a better understanding of all aspects of pruritus generation, transmission and recognition. In the case of pruritus caused by dermatitis, immune cells infiltrating the skin secrete inflammatory cytokines, which also act on peripheral nerves as pruritus mediators and induce an inflammatory response. Interestingly, there has been accumulating evidence that peripheral nerves are also involved in the inflammation via neuropeptides. In this article, we summarize the findings on pruritus mediators secreted by immune cells and the roles of peripheral nerves in pruritus in terms of their interactions with immunity.
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Nervios Periféricos/inmunología , Prurito/inmunología , Animales , HumanosRESUMEN
Amyloidosis is a group of diseases that includes Alzheimer's disease, prion diseases, transthyretin (ATTR) amyloidosis, and immunoglobulin light chain (AL) amyloidosis. The mechanism of organ dysfunction resulting from amyloidosis has been a topic of debate. This review focuses on the ultrastructure of tissue damage resulting from amyloid deposition and therapeutic insights based on the pathophysiology of amyloidosis. Studies of nerve biopsy or cardiac autopsy specimens from patients with ATTR and AL amyloidoses show atrophy of cells near amyloid fibril aggregates. In addition to the stress or toxicity attributable to amyloid fibrils themselves, the toxicity of non-fibrillar states of amyloidogenic proteins, particularly oligomers, may also participate in the mechanisms of tissue damage. The obscuration of the basement and cytoplasmic membranes of cells near amyloid fibrils attributable to an affinity of components constituting these membranes to those of amyloid fibrils may also play an important role in tissue damage. Possible major therapeutic strategies based on pathophysiology of amyloidosis consist of the following: (1) reducing or preventing the production of causative proteins; (2) preventing the causative proteins from participating in the process of amyloid fibril formation; and/or (3) eliminating already-deposited amyloid fibrils. As the development of novel disease-modifying therapies such as short interfering RNA, antisense oligonucleotide, and monoclonal antibodies is remarkable, early diagnosis and appropriate selection of treatment is becoming more and more important for patients with amyloidosis.
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Enfermedad de Alzheimer/patología , Neuropatías Amiloides Familiares/patología , Amiloide/inmunología , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/patología , Miocardio/patología , Nervios Periféricos/patología , Enfermedades por Prión/patología , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/inmunología , Amiloide/antagonistas & inhibidores , Amiloide/genética , Neuropatías Amiloides Familiares/tratamiento farmacológico , Neuropatías Amiloides Familiares/genética , Neuropatías Amiloides Familiares/inmunología , Benzoxazoles/uso terapéutico , Diflunisal/uso terapéutico , Humanos , Cadenas Ligeras de Inmunoglobulina/genética , Cadenas Ligeras de Inmunoglobulina/metabolismo , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/tratamiento farmacológico , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/genética , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/inmunología , Factores Inmunológicos/uso terapéutico , Miocardio/inmunología , Fármacos Neuroprotectores/uso terapéutico , Oligonucleótidos/uso terapéutico , Nervios Periféricos/efectos de los fármacos , Nervios Periféricos/inmunología , Prealbúmina/antagonistas & inhibidores , Prealbúmina/genética , Prealbúmina/inmunología , Enfermedades por Prión/tratamiento farmacológico , Enfermedades por Prión/genética , Enfermedades por Prión/inmunología , ARN Interferente Pequeño/uso terapéuticoRESUMEN
Guillain-Barré syndrome (GBS) is an autoimmune disease in which the peripheral nerves are affected. GBS has different subtypes, such as acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN). Infections, e.g. Campylobacter jejuni, influenza, etc., can lead to GBS. Both environmental and genetic factors play a major role in the occurrence of GBS. Several studies have investigated the genetic basis of GBS. Human leukocyte antigens (HLA) genes, Cluster of Differentiation (CD) 1A, FAS, Fc gamma receptors (FcGR), Intercellular adhesion molecule-1 (ICAM1), different interleukins, Nucleotide oligomerization domain (NOD), Toll-like receptor 4 (TLR4), Tumor necrosis factor-α (TNF-α) are among the genes reported to be involved in susceptibility to the disease. Dysregulation and dysfunction of the mentioned gene products, even though their role in the pathogenesis of GBS is controversial, play a role in inflammatory pathways, regulation of immune cells and system, antigen presentation, axonal degeneration, apoptosis, and cross-reaction. This review aims to summarize associated genes with GBS to contribute to better understanding of GBS pathogenesis and discover the gene pathways that play role in GBS occurrence.
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Interacción Gen-Ambiente , Predisposición Genética a la Enfermedad/genética , Síndrome de Guillain-Barré/genética , Síndrome de Guillain-Barré/inmunología , Mediadores de Inflamación/inmunología , Humanos , Nervios Periféricos/inmunologíaRESUMEN
OBJECTIVE: To explore the spectrum of skeletal muscle and nerve pathology of patients who died after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and to assess for direct viral invasion of these tissues. METHODS: Psoas muscle and femoral nerve sampled from 35 consecutive autopsies of patients who died after SARS-CoV-2 infection and 10 SARS-CoV-2-negative controls were examined under light microscopy. Clinical and laboratory data were obtained by chart review. RESULTS: In SARS-CoV-2-positive patients, mean age at death was 67.8 years (range 43-96 years), and the duration of symptom onset to death ranged from 1 to 49 days. Four patients had neuromuscular symptoms. Peak creatine kinase was elevated in 74% (mean 959 U/L, range 29-8,413 U/L). Muscle showed type 2 atrophy in 32 patients, necrotizing myopathy in 9, and myositis in 7. Neuritis was seen in 9. Major histocompatibility complex-1 (MHC-1) expression was observed in all cases of necrotizing myopathy and myositis and in 8 additional patients. Abnormal expression of myxovirus resistance protein A (MxA) was present on capillaries in muscle in 9 patients and in nerve in 7 patients. SARS-CoV-2 immunohistochemistry was negative in muscle and nerve in all patients. In the 10 controls, muscle showed type 2 atrophy in all patients, necrotic muscle fibers in 1, MHC-1 expression in nonnecrotic/nonregenerating fibers in 3, MxA expression on capillaries in 2, and inflammatory cells in none, and nerves showed no inflammatory cells or MxA expression. CONCLUSIONS: Muscle and nerve tissue demonstrated inflammatory/immune-mediated damage likely related to release of cytokines. There was no evidence of direct SARS-CoV-2 invasion of these tissues. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that muscle and nerve biopsies document a variety of pathologic changes in patients dying of coronavirus disease 2019 (COVID-19).
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COVID-19/patología , Músculo Esquelético/patología , Nervios Periféricos/patología , Adulto , Anciano , Anciano de 80 o más Años , Autopsia , COVID-19/inmunología , COVID-19/virología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/inmunología , Músculo Esquelético/virología , Nervios Periféricos/inmunología , Nervios Periféricos/virologíaRESUMEN
In recent decades, cancer research has expanded exponentially beyond the study of abnormally dividing cells to include complex and extensive heterotypic interactions between cancer and noncancer cells that constitute the tumor microenvironment (TME). Modulation of stromal, immune, and endothelial cells by cancer cells promotes proliferation, survival, and metabolic changes that support tumor growth and metastasis. Recent evidence demonstrates that tumors can recruit peripheral nerves to the TME, leading to enhanced tumor growth in a range of cancer models through distinct mechanisms. This process, termed tumor innervation, is associated with an aggressive tumor phenotype and correlates with poor prognosis in clinical studies. Therefore, the peripheral nervous system may play an underrecognized role in cancer development, harboring targetable pathways that warrant investigation. To date, nerves have been implicated in driving proliferation, invasion, metastasis, and immune evasion through locally delivered neurotransmitters. However, emerging evidence suggests that cell-cell communication via exosomes induces tumor innervation, and thus exosomes may also mediate neural regulation of the TME. In this Review, seminal studies establishing tumor innervation are discussed, and known and putative signaling mechanisms between peripheral nerves and components of the TME are explored as a means to identify potential opportunities for therapeutic intervention.
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Proliferación Celular , Neoplasias , Nervios Periféricos , Escape del Tumor , Microambiente Tumoral/inmunología , Humanos , Invasividad Neoplásica , Metástasis de la Neoplasia , Neoplasias/inmunología , Neoplasias/metabolismo , Neoplasias/patología , Nervios Periféricos/inmunología , Nervios Periféricos/metabolismo , Nervios Periféricos/patologíaRESUMEN
Although macrophages (MΦ) are known to play a central role in neuropathic pain, their contribution to cancer pain has not been established. Here we report that depletion of sciatic nerve resident MΦs (rMΦ) in mice attenuates mechanical/cold hypersensitivity and spontaneous pain evoked by intraplantar injection of melanoma or lung carcinoma cells. MΦ-colony stimulating factor (M-CSF) was upregulated in the sciatic nerve trunk and mediated cancer-evoked pain via rMΦ expansion, transient receptor potential ankyrin 1 (TRPA1) activation, and oxidative stress. Targeted deletion of Trpa1 revealed a key role for Schwann cell TRPA1 in sciatic nerve rMΦ expansion and pain-like behaviors. Depletion of rMΦs in a medial portion of the sciatic nerve prevented pain-like behaviors. Collectively, we identified a feed-forward pathway involving M-CSF, rMΦ, oxidative stress, and Schwann cell TRPA1 that operates throughout the nerve trunk to signal cancer-evoked pain. SIGNIFICANCE: Schwann cell TRPA1 sustains cancer pain through release of M-CSF and oxidative stress, which promote the expansion and the proalgesic actions of intraneural macrophages. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/12/3387/F1.large.jpg.
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Dolor en Cáncer/patología , Hiperalgesia/patología , Macrófagos/inmunología , Melanoma Experimental/complicaciones , Nervios Periféricos/inmunología , Células de Schwann/inmunología , Canal Catiónico TRPA1/fisiología , Animales , Dolor en Cáncer/etiología , Dolor en Cáncer/metabolismo , Femenino , Hiperalgesia/etiología , Hiperalgesia/metabolismo , Neoplasias Pulmonares/complicaciones , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
BACKGROUND: Lipopolysaccharide (LPS) endotoxins are activators of innate immunity inducing infection and inflammatory responses. Anti-inflammatory drugs can have undesirable side effects. Acupuncture may be an alternative for the treatment of inflammatory processes. OBJECTIVE: We investigated the potential anti-inflammatory effect of manual acupuncture (MA) at SP6 upon LPS-induced peritonitis in rats. METHODS: Peritonitis was induced in rats with an intraperitoneal injection of LPS (0.002, 0.02, 0.2 or 2 µg/kg) in four experimental groups (n = 6 each). A fifth group was injected with sterile saline solution (saline group, n = 6). Four hours after the procedure, peritoneal fluid was collected to determine total cell counts for inflammatory cells, differential leukocyte counts and peritoneal capillary permeability. The LPS dose of 0.02 µg/kg was used in the subsequent experiments as it most successfully induced peritoneal inflammation. Subsequently, five experimental groups (n = 12 rats each) were used: (1) saline, (2) control (untreated LPS group), (3) indomethacin (LPS group treated with indomethacin), (4) NA (LPS group treated with MA at a location not corresponding to any traditional acupuncture point), and (5) SP6 (LPS group treated with verum MA at SP6). Ten minutes after MA or 30 min after indomethacin treatment, the rats received an intraperitoneal injection of LPS. After 4 h, total leukocyte and differential cell counts, myeloperoxidase (MPO) activity, vascular permeability and cytokine levels were evaluated in the peritoneal fluid. Cytokine levels were additionally evaluated in the brainstem. RESULTS: SP6 MA and indomethacin treatments reduced inflammatory cell infiltration, vascular permeability and MPO activity in the LPS-exposed rats. Pre-treatment with indomethacin and SP6 MA decreased tumor necrosis factor (TNF)-α levels and preserved interleukin (IL)-10 in the peritoneal fluid. Indomethacin also reduced IL-6 in the peritoneal fluid. In the brainstem, indomethacin reduced IL-1ß, IL-6, TNFα and IL-10, whereas SP6 MA reduced only TNFα and IL-6 levels. CONCLUSIONS: This study clearly demonstrates the anti-inflammatory effect of acupuncture, which we believe may involve the activation of anti-inflammatory neural reflexes in the regulation of peritonitis.
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Terapia por Acupuntura , Tronco Encefálico/inmunología , Citocinas/inmunología , Nervios Periféricos/inmunología , Peritonitis/terapia , Puntos de Acupuntura , Animales , Citocinas/genética , Humanos , Lipopolisacáridos/efectos adversos , Masculino , Peritonitis/genética , Peritonitis/inmunología , Ratas , Ratas WistarRESUMEN
Immunohistochemical staining is widely used to identify opioid receptors in specific cell types throughout the nervous system. Opioid receptors are not restricted to the central nervous system, but are also present in peripheral sensory neurons, where their activation exerts analgesic effects without inducing centrally mediated side effects. Here, we describe immunohistochemical analysis of µ-opioid receptors in the peripheral sensory neuron cell bodies, along the axons and their peripheral endings in the hind paw skin, as well as in the spinal cord, under naïve and sciatic nerve damage conditions in mice. Importantly, we consider the ongoing debate on the specificity of antibodies.
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Inmunohistoquímica/métodos , Nervios Periféricos/metabolismo , Receptores Opioides mu/inmunología , Analgésicos Opioides/metabolismo , Animales , Axones/metabolismo , Ganglios Espinales/citología , Humanos , Ratones , Nervios Periféricos/inmunología , Receptores Acoplados a Proteínas G/metabolismo , Receptores Opioides/inmunología , Receptores Opioides/metabolismo , Receptores Opioides mu/metabolismo , Nervio Ciático/citología , Neuropatía Ciática , Células Receptoras Sensoriales/metabolismo , Médula Espinal/metabolismoRESUMEN
The highly neurotropic rabies virus (RABV) enters peripheral neurons at axon termini and requires long distance axonal transport and trans-synaptic spread between neurons for the infection of the central nervous system (CNS). Recent 3D imaging of field RABV-infected brains revealed a remarkably high proportion of infected astroglia, indicating that highly virulent field viruses are able to suppress astrocyte-mediated innate immune responses and virus elimination pathways. While fundamental for CNS invasion, in vivo field RABV spread and tropism in peripheral tissues is understudied. Here, we used three-dimensional light sheet and confocal laser scanning microscopy to investigate the in vivo distribution patterns of a field RABV clone in cleared high-volume tissue samples after infection via a natural (intramuscular; hind leg) and an artificial (intracranial) inoculation route. Immunostaining of virus and host markers provided a comprehensive overview of RABV infection in the CNS and peripheral nerves after centripetal and centrifugal virus spread. Importantly, we identified non-neuronal, axon-ensheathing neuroglia (Schwann cells, SCs) in peripheral nerves of the hind leg and facial regions as a target cell population of field RABV. This suggests that virus release from axons and infected SCs is part of the RABV in vivo cycle and may affect RABV-related demyelination of peripheral neurons and local innate immune responses. Detection of RABV in axon-surrounding myelinating SCs after i.c. infection further provided evidence for anterograde spread of RABV, highlighting that RABV axonal transport and spread of infectious virus in peripheral nerves is not exclusively retrograde. Our data support a new model in which, comparable to CNS neuroglia, SC infection in peripheral nerves suppresses glia-mediated innate immunity and delays antiviral host responses required for successful transport from the peripheral infection sites to the brain.
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Transporte Axonal , Encéfalo/virología , Inmunidad Innata/inmunología , Neuroglía/virología , Neuronas/virología , Nervios Periféricos/virología , Virus de la Rabia/patogenicidad , Tropismo Viral , Animales , Axones/metabolismo , Axones/patología , Axones/virología , Encéfalo/inmunología , Encéfalo/patología , Imagenología Tridimensional , Ratones , Microscopía Confocal , Neuroglía/inmunología , Neuroglía/patología , Neuronas/metabolismo , Neuronas/patología , Nervios Periféricos/inmunología , Nervios Periféricos/patología , ARN Viral , Rabia , Células de Schwann/inmunología , Células de Schwann/patología , Células de Schwann/virologíaRESUMEN
BACKGROUND: Experimental autoimmune encephalomyelitis (EAE) is the most commonly used and clinically relevant murine model for human multiple sclerosis (MS), a demyelinating autoimmune disease characterized by mononuclear cell infiltration into the central nervous system (CNS). The aim of the present study was to appraise the alterations, poorly documented in the literature, which may occur at the peripheral nervous system (PNS) level. METHODS: To this purpose, a multiple evaluation of peripheral nerve excitability was undertaken, by means of a minimally invasive electrophysiological method, in EAE mice immunized with the myelin oligodendrocyte glycoprotein (MOG) 35-55 peptide, an experimental model for MS that reproduces, in animals, the anatomical and behavioral alterations observed in humans with MS, including CNS inflammation, demyelination of neurons, and motor abnormalities. Additionally, the myelin sheath thickness of mouse sciatic nerves was evaluated using transmission electronic microscopy. RESULTS: As expected, the mean clinical score of mice, daily determined to describe the symptoms associated to the EAE progression, increased within about 18 days after immunization for EAE mice while it remained null for all control animals. The multiple evaluation of peripheral nerve excitability, performed in vivo 2 and 4 weeks after immunization, reveals that the main modifications of EAE mice, compared to control animals, are a decrease of the maximal compound action potential (CAP) amplitude and of the stimulation intensity necessary to generate a CAP with a 50% maximum amplitude. In addition, and in contrast to control mice, at least 2 CAPs were recorded following a single stimulation in EAE animals, reflecting various populations of sensory and motor nerve fibers having different CAP conduction speeds, as expected if a demyelinating process occurred in the PNS of these animals. In contrast, single CAPs were always recorded from the sensory and motor nerve fibers of control mice having more homogeneous CAP conduction speeds. Finally, the myelin sheath thickness of sciatic nerves of EAE mice was decreased 4 weeks after immunization when compared to control animals. CONCLUSIONS: In conclusion, the loss of immunological self-tolerance to MOG in EAE mice or in MS patients may not be only attributed to the restricted expression of this antigen in the immunologically privileged environment of the CNS but also of the PNS.
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Potenciales de Acción/fisiología , Encefalomielitis Autoinmune Experimental/fisiopatología , Conducción Nerviosa/fisiología , Nervios Periféricos/fisiopatología , Animales , Progresión de la Enfermedad , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Ratones , Músculo Esquelético/inmunología , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Vaina de Mielina/inmunología , Vaina de Mielina/patología , Glicoproteína Mielina-Oligodendrócito/inmunología , Fragmentos de Péptidos/inmunología , Nervios Periféricos/inmunología , Nervios Periféricos/patologíaRESUMEN
Class I PI3K enzymes are critical for the maintenance of effective immunity. In T cells, PI3Kα and PI3Kδ are activated by the TCR and costimulatory receptors, whereas PI3Kγ is activated by G protein-coupled chemokine receptors. PI3Kδ is a key regulator of regulatory T (Treg) cell function. PI3K isoform-selective inhibitors are in development for the treatment of diseases associated with immune dysregulation, including chronic inflammatory conditions, cancer, and autoimmune diseases. Idelalisib (PI3Kδ), alpelisib (PI3Kα), duvelisib (PI3Kδ/γ), and copanlisib (pan-PI3K) have recently been approved for use in cancer treatment. Although effective, these therapies often have severe side effects associated with immune dysregulation and, in particular, loss of Treg cells. Therefore, it is important to gain a better understanding of the relative contribution of different PI3K isoforms under homeostatic and inflammatory conditions. Experimental autoimmune encephalitis is a mouse model of T cell-driven CNS inflammation, in which Treg cells play a key protective role. In this study, we show that PI3Kδ is required to maintain normal Treg cell development and phenotype under homeostatic conditions but that loss of PI3Kδ alone in Treg cells does not lead to autoimmunity. However, combined loss of PI3Kα and PI3Kδ signaling resulted in increased experimental autoimmune encephalitis disease severity. Moreover, mice lacking PI3Kα and PI3Kδ in Treg cells developed spontaneous peripheral nerve inflammation. These results show a key role for PI3K signaling in Treg cell-mediated protection against CNS inflammation.
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Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Fosfatidilinositol 3-Quinasa Clase Ib/metabolismo , Encefalomielitis Autoinmune Experimental/inmunología , Nervios Periféricos/inmunología , Linfocitos T Reguladores/inmunología , Animales , Autoinmunidad/genética , Fosfatidilinositol 3-Quinasa Clase I/genética , Fosfatidilinositol 3-Quinasa Clase Ib/genética , Encefalomielitis Autoinmune Experimental/sangre , Encefalomielitis Autoinmune Experimental/diagnóstico , Encefalomielitis Autoinmune Experimental/patología , Femenino , Humanos , Masculino , Ratones , Ratones Transgénicos , Glicoproteína Mielina-Oligodendrócito/administración & dosificación , Glicoproteína Mielina-Oligodendrócito/inmunología , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/inmunología , Nervios Periféricos/patología , Índice de Severidad de la Enfermedad , Transducción de Señal/genética , Transducción de Señal/inmunología , Linfocitos T Reguladores/metabolismoRESUMEN
Anti-myelin-associated glycoprotein (MAG) neuropathy is a disabling autoimmune peripheral neuropathy that is caused by circulating monoclonal IgM autoantibodies directed against the human natural killer-1 (HNK-1) epitope. This carbohydrate epitope is highly expressed on adhesion molecules such as MAG, a glycoprotein present in myelinated nerves. We previously showed the therapeutic potential of the glycopolymer poly(phenyl disodium 3-O-sulfo-ß-d-glucopyranuronate)-(1â3)-ß-d-galactopyranoside (PPSGG) in selectively neutralizing anti-MAG IgM antibodies in an immunological mouse model and ex vivo with sera from anti-MAG neuropathy patients. PPSGG is composed of a biodegradable backbone that multivalently presents a mimetic of the HNK-1 epitope. In this study, we further explored the pharmacodynamic properties of the glycopolymer and its ability to inhibit the binding of anti-MAG IgM to peripheral nerves. The polymer selectively bound anti-MAG IgM autoantibodies and prevented the binding of patients' anti-MAG IgM antibodies to myelin of non-human primate sciatic nerves. Upon PPSGG treatment, neither activation nor inhibition of human and murine peripheral blood mononuclear cells nor alteration of systemic inflammatory markers was observed in mice or ex vivo in human peripheral blood mononuclear cells. Intravenous injections of PPSGG to mice immunized against the HNK-1 epitope removed anti-MAG IgM antibodies within less than 1 hr, indicating a fast and efficient mechanism of action as compared to a B-cell depletion with anti-CD20. In conclusion, these observations corroborate the therapeutic potential of PPSGG for an antigen-specific treatment of anti-MAG neuropathy. Read the Editorial Highlight for this article on page 465.
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Anticuerpos Monoclonales/inmunología , Leucocitos Mononucleares/metabolismo , Vaina de Mielina/metabolismo , Enfermedades del Sistema Nervioso Periférico/inmunología , Autoanticuerpos/inmunología , Glicoproteínas/metabolismo , Humanos , Inmunoglobulina M/inmunología , Leucocitos Mononucleares/inmunología , Nervios Periféricos/inmunologíaRESUMEN
The mature peripheral nervous system is a steady network structure yet shows remarkable regenerative properties. The interaction of peripheral nerves with myeloid cells has largely been investigated in the context of damage, following trauma or infection. Recently, specific macrophages dedicated to homeostatic peripheral nerves have come into focus. These macrophages are defined by tissue and nerve type, are seeded in part prenatally, and self-maintain via proliferation. Thus, they are markedly distinct from monocyte-derived macrophages invading after local disturbance of nerve integrity. The phenotypic and transcriptional adaptation of macrophages to the discrete nervous niche may exert axon guidance and nerve regeneration and thus contribute to the stability of the peripheral nervous network. Deciphering these conserved macrophage-nerve interactions offers new translational perspectives for chronic diseases of the peripheral nervous system, such as diabetic neuropathy and pain.
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Macrófagos/citología , Macrófagos/inmunología , Neuroinmunomodulación/inmunología , Nervios Periféricos/inmunología , Animales , Diferenciación Celular/inmunología , HumanosRESUMEN
BACKGROUND AND PURPOSE: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a heterogeneous autoimmune disorder critically lacking diagnostic biomarkers. Autoantibodies to nodal and paranodal components have recently been described in a small subset of patients. Here, the diagnostic value of immune reactivity toward the myelin compartment was investigated. METHODS: Ninety-four French CIDP patients were retrospectively studied. The reactivity toward the peripheral nerve was investigated. Sural nerve biopsies were examined by electron microscopy and immunofluorescence. RESULTS: Twenty-one patients (22%) and three patients (3%) presented with a strong immunoglobulin G or immunoglobulin M reactivity respectively against the myelin compartment. The clinical, electrophysiological and morphological features were examined in nine of these patients for whom sural nerve biopsies were available. Seven patients were electrodiagnosed with definite CIDP, one with possible CIDP and one was unclassifiable but sural nerve biopsy argued for CIDP diagnosis. Electron microscopy of sural nerve biopsies demonstrated the presence of macrophage-mediated demyelination restricted to the internode in all nine patients. Immunolabelling for voltage-gated sodium channels, myelin and axonal markers confirmed the presence of segmental demyelination and of remyelination. The nodal and paranodal regions, however, were unaffected in these patients. Nerve conduction studies corroborated the multifocal and segmental profile, and seven patients showed increased duration of proximal (1.5-5.1 times) and/or distal (1.2-3.4 times) compound muscle action potential in at least two nerves. CONCLUSION: Antibody- and macrophage-mediated demyelination appears responsible for conduction alterations in CIDP patients and nerve immunostaining assays may serve as a supportive diagnostic biomarker.
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Autoanticuerpos , Axones/patología , Macrófagos/patología , Vaina de Mielina/patología , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/diagnóstico , Adulto , Anciano , Axones/inmunología , Electrodiagnóstico , Femenino , Humanos , Inmunoglobulina G/inmunología , Macrófagos/inmunología , Masculino , Persona de Mediana Edad , Vaina de Mielina/inmunología , Conducción Nerviosa , Nervios Periféricos/inmunología , Nervios Periféricos/patología , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/inmunología , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/patología , Estudios RetrospectivosRESUMEN
OBJECTIVE: To define the clinicopathologic features of amphiphysin-immunoglobulin G (IgG)-mediated neuropathy. METHODS: Patients examined at our institution from January 1, 1995, to September 30, 2018, with amphiphysin-IgG by indirect immunofluorescence and Western blot, were reviewed. Their phenotypes were compared to cases of coexisting collapsin response-mediator protein-5 (CRMP5)-IgG or anti-neuronal nuclear antibody type 1 (ANNA1-IgG) and CRMP5-IgG autoimmunity. Improvement in modified Rankin Scale (mRS) (≥1) on follow-up was considered a favorable outcome. Amphiphysin RNA expression was assessed in healthy nerves. RESULTS: Fifty-three amphiphysin-IgG-positive cases were identified. Of 33 (60%) patients with neuropathy, 21 had amphiphysin-IgG alone, and 12 had coexisting autoantibodies (ANNA1-IgG, n = 8; CRMP5-IgG, n = 2; ANNA1-IgG and CRMP5-IgG, n = 2). The neuropathies in isolated amphiphysin-IgG autoimmunity included polyradiculoneuropathy (62%), diffuse sensory neuronopathy (35%), and facial neuropathy with gastroparesis (3%). Among these, pain (80%), breast cancer (63%), and CNS (57%) involvements commonly coexisted, and neuropathy frequently prompted breast cancer diagnosis (76%). Stiff-person spectrum disorder was the most common CNS accompaniment (45%). Nerve biopsies showed axonal loss (n = 6/6), subperineurial edema (n = 4/6), and CD4 predominant inflammation (n = 2/6). Median mRS score at last follow-up was 3.5; 58% of patients were immunotherapy-responsive. Patients with amphiphysin-IgG alone had more favorable immunotherapy response than patients with CRMP5-IgG polyneuropathy (n = 45) (44% vs 16%, p = 0.028, odds ratio 4.2, 95% confidence interval 1.1 to 15.5). Only 1/9 (11%) patients with amphiphysin-IgG with coexisting CRMP5-IgG or ANNA1-IgG had immunotherapy response. RNA amphiphysin expression occurred at low levels in nerve. CONCLUSION: Amphiphysin-IgG autoimmune neuropathy has a recognizable phenotype, is frequently immune responsive, and can prompt early diagnosis of breast cancer.
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Autoanticuerpos/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Proteínas del Tejido Nervioso/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Antinucleares/inmunología , Anticuerpos Antineoplásicos , Enfermedades Autoinmunes del Sistema Nervioso/epidemiología , Enfermedades Autoinmunes del Sistema Nervioso/patología , Enfermedades Autoinmunes del Sistema Nervioso/fisiopatología , Biopsia , Neoplasias de la Mama/epidemiología , Comorbilidad , Enfermedades del Nervio Facial/epidemiología , Enfermedades del Nervio Facial/inmunología , Enfermedades del Nervio Facial/patología , Enfermedades del Nervio Facial/fisiopatología , Femenino , Humanos , Hidrolasas/inmunología , Inmunoglobulina G/inmunología , Masculino , Proteínas Asociadas a Microtúbulos/inmunología , Persona de Mediana Edad , Proteínas del Tejido Nervioso/genética , Dolor , Nervios Periféricos/inmunología , Nervios Periféricos/metabolismo , Nervios Periféricos/patología , Polirradiculoneuropatía/epidemiología , Polirradiculoneuropatía/inmunología , Polirradiculoneuropatía/patología , Polirradiculoneuropatía/fisiopatología , Síndrome de la Persona Rígida/epidemiología , SíndromeRESUMEN
OBJECTIVE: The present study aimed to evaluate the analgesic and anti-inflammatory effects of far infrared-emitting ceramics (cFIRs) in a model of persistent inflammatory hyperalgesia and to elucidate the possible mechanisms of these effects. METHODS: Mice were injected with complete Freund's adjuvant (CFA) and treated with cFIRs via placement on a pad impregnated with cFIRs on the bottom of the housing unit for different periods of time. Mice underwent mechanical hyperalgesia and edema assessments, and tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and IL-10 levels were measured. Twenty-four hours after CFA injection and 30â¯min before cFIR treatment, mice were pretreated with a nonselective adenosinergic antagonist, caffeine, the selective adenosine receptor A1 antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), the selective cannabinoid receptor type 1 antagonist, AM281, the selective cannabinoid receptor type 2 antagonist, AM630, or the nonselective opioid receptor antagonist, naloxone, and mechanical hyperalgesia was assessed. RESULTS: cFIRs statistically (Pâ¯<â¯0.05) decreased CFA-induced mechanical hyperalgesia ((82.86⯱â¯5.21)% in control group vs (56.67⯱â¯9.54)% in cFIR group) and edema ((1699.0⯱â¯77.8) µm in control group vs (988.7⯱â¯107.6)⯵m in cFIR group). cFIRs statistically (Pâ¯<â¯0.05) reduced TNF-α ((0.478⯱â¯0.072)â¯pg/mg of protein in control group vs (0.273⯱â¯0.055)â¯pg/mg of protein in cFIR group) and IL-1ß ((95.81⯱â¯3.95)â¯pg/mg of protein in control group vs (80.61⯱â¯4.71)â¯pg/mg of protein in cFIR group) levels and statistically (Pâ¯<â¯0.05) increased IL-10 ((18.32⯱â¯0.78)â¯pg/mg of protein in control group vs (25.89⯱â¯1.23)â¯pg/mg of protein in cFIR group) levels in post-CFA-injected paws. Peripheral pre-administration of inhibitory neuroreceptor antagonists (caffeine, DPCPX, AM281, AM630 and naloxone) prevented the analgesic effects of cFIRs (Pâ¯<â¯0.05). CONCLUSION: These data provide additional support for the use of cFIRs in the treatment of painful inflammatory conditions and contribute to our understanding of the neurobiological mechanisms of the therapeutic effects of cFIRs.
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Cerámica/química , Citocinas/inmunología , Adyuvante de Freund/efectos adversos , Hiperalgesia/inmunología , Hiperalgesia/terapia , Células Receptoras Sensoriales/inmunología , Animales , Cerámica/efectos de la radiación , Citocinas/genética , Modelos Animales de Enfermedad , Humanos , Hiperalgesia/inducido químicamente , Rayos Infrarrojos , Interleucina-10/genética , Interleucina-10/inmunología , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Masculino , Ratones , Manejo del Dolor , Nervios Periféricos/inmunología , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
Autoimmune diseases of the nervous system in children are composed of a heterogeneous group of rare disorders that can affect the central or peripheral nervous system at any level. Presentations may occur in children of any age and are typically acute or subacute in onset. Consideration of an autoimmune process as the etiology of neurologic diseases in children is important, as it may lead to early initiation of immunotherapy and an improvement in long-term neurologic outcomes. The developing nervous and immune systems in children create unique challenges in diagnosis and treatment of these rare diseases. In this review, autoimmune diseases affecting the brain, spinal cord, nerve roots, peripheral nerves, neuromuscular junction, and muscle in children are described.