RESUMEN
Neuroinflammation is a recognized pathogenic mechanism underlying motor neuron degeneration in amyotrophic lateral sclerosis (ALS), but the inflammatory mechanisms influencing peripheral motor axon degeneration remain largely unknown. A recent report showed a pathogenic role for c-Kit-expressing mast cells mediating inflammation and neuromuscular junction denervation in muscles from SOD1G93A rats. Here, we have explored whether mast cells infiltrate skeletal muscles in autopsied muscles from ALS patients. We report that degranulating mast cells were abundant in the quadriceps muscles from ALS subjects but not in controls. Mast cells were associated with myofibers and motor endplates and, remarkably, interacted with neutrophils forming large extracellular traps. Mast cells and neutrophils were also abundant around motor axons in the extensor digitorum longus muscle, sciatic nerve, and ventral roots of symptomatic SOD1G93A rats, indicating that immune cell infiltration extends along the entire peripheral motor pathway. Postparalysis treatment of SOD1G93A rats with the tyrosine kinase inhibitor drug masitinib prevented mast cell and neutrophil infiltration, axonal pathology, secondary demyelination, and the loss of type 2B myofibers, compared with vehicle-treated rats. These findings provide further evidence for a yet unrecognized contribution of immune cells in peripheral motor pathway degeneration that can be therapeutically targeted by tyrosine kinase inhibitors.
Asunto(s)
Esclerosis Amiotrófica Lateral/inmunología , Mastocitos/inmunología , Neuronas Motoras/patología , Unión Neuromuscular/patología , Neutrófilos/inmunología , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/patología , Animales , Axones/efectos de los fármacos , Axones/inmunología , Axones/patología , Benzamidas , Degranulación de la Célula/efectos de los fármacos , Degranulación de la Célula/inmunología , Modelos Animales de Enfermedad , Humanos , Masculino , Mastocitos/efectos de los fármacos , Neuronas Motoras/citología , Neuronas Motoras/inmunología , Músculo Esquelético/citología , Músculo Esquelético/inervación , Músculo Esquelético/patología , Unión Neuromuscular/efectos de los fármacos , Unión Neuromuscular/inmunología , Infiltración Neutrófila/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Piperidinas , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas , Ratas , Ratas Transgénicas , Superóxido Dismutasa/genética , Superóxido Dismutasa-1/genética , Tiazoles/farmacología , Tiazoles/uso terapéutico , Resultado del TratamientoRESUMEN
In recent decades, several neurodegenerative diseases have been shown to be exacerbated by systemic inflammatory processes. There is a wide range of literature that demonstrates a clear but complex relationship between the central nervous system (CNS) and the immunological system, both under naïve or pathological conditions. In diseased brains, peripheral inflammation can transform "primed" microglia into an "active" state, which can trigger stronger pathological responses. Demyelinating diseases are a group of neurodegenerative diseases characterized by inflammatory lesions associated with demyelination, which in turn induces axonal damage, neurodegeneration, and progressive loss of function. Among them, the most important are multiple sclerosis (MS) and neuromyelitis optica (NMO). In this review, we will analyze the effect of specific peripheral inflammatory stimuli in the progression of demyelinating diseases and discuss their animal models. In most cases, peripheral immune stimuli are exacerbating.
Asunto(s)
Envejecimiento/inmunología , Encéfalo/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Microglía/inmunología , Esclerosis Múltiple/inmunología , Neuromielitis Óptica/inmunología , Envejecimiento/patología , Animales , Axones/inmunología , Axones/patología , Encéfalo/patología , Comunicación Celular , Encefalomielitis Autoinmune Experimental/patología , Humanos , Sistema Hipotálamo-Hipofisario/inmunología , Sistema Hipotálamo-Hipofisario/patología , Sistema Inmunológico/patología , Inflamación , Microglía/patología , Esclerosis Múltiple/patología , Neuromielitis Óptica/patología , Obesidad/inmunología , Obesidad/patología , Sistema Hipófiso-Suprarrenal/inmunología , Sistema Hipófiso-Suprarrenal/patologíaRESUMEN
BACKGROUND: Endemic pemphigus foliaceus (EPF), is also known as "fogo selvagem" or "wild fire," reflecting the intense burning sensation of the skin reported by patients with this disease. Based on this finding, we tested for neural autoreactivity in patients affected by a new variant of EPF (El Bagre-EPF). METHODS: We tested 20 El Bagre-EPF patients, 20 normal controls from the endemic area, and 20 age- and sex-matched normal controls from outside the endemic area. We tested for autoreactivity to several immunoglobulins and complement. Both human skin and bovine tail were used as antigens. RESULTS: We detected autoreactivity to neural structures, mechanoreceptors, nerves, perineural cell layers of the arachnoid envelope around the optic nerve, brain structures, and to neuromuscular spindles; these structures colocalized with several neural markers. The patient antibodies also colocalized with desmoplakins 1 and 2, with the armadillo repeat protein deleted in velo-cardio-facial syndrome and with p0071 antibodies. Autoreactivity was also found associated with neurovascular bundles innervating the skin, and immunoelectron microscopy using protein A gold against patient antibodies was positive against the nerve axons. Paucicellularity of the intraepidermal nerve endings and defragmentation of the neural plexus were seen in 70% of the cases and not in the controls from the endemic area (p<0.005). Neuropsychological and/or behavioral symptoms were detected in individuals from the endemic area, including sensorimotor axonal neuropathy. CONCLUSIONS: Our findings may explain for the first time the "pose of pemphigus," representing a dorsiflexural posture seen in EPF patients vis-a-vis the weakness of the extensor nerves, and furthermore, the autoreactivity to nerves in EPF could explain the "burning sensation" encountered in EPF disease.
Asunto(s)
Antígenos/inmunología , Autoanticuerpos/inmunología , Plexo Coroideo/inmunología , Desmoplaquinas/metabolismo , Enfermedades Endémicas , Nervio Óptico/inmunología , Corpúsculos de Pacini/inmunología , Pénfigo , Piel/inmunología , Adulto , Animales , Antígenos/análisis , Antígenos/metabolismo , Autoanticuerpos/análisis , Autoanticuerpos/metabolismo , Axones/inmunología , Axones/patología , Antígenos CD57/genética , Antígenos CD57/inmunología , Antígenos CD57/metabolismo , Estudios de Casos y Controles , Bovinos , Plexo Coroideo/efectos de los fármacos , Plexo Coroideo/patología , Colombia/epidemiología , Desmoplaquinas/genética , Femenino , Proteína Ácida Fibrilar de la Glía/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Humanos , Inmunoglobulinas/análisis , Inmunoglobulinas/inmunología , Inmunoglobulinas/metabolismo , Inmunohistoquímica , Masculino , Mercurio/efectos adversos , Microscopía Inmunoelectrónica , Persona de Mediana Edad , Proteína Básica de Mielina/genética , Proteína Básica de Mielina/metabolismo , Nervio Óptico/efectos de los fármacos , Nervio Óptico/patología , Corpúsculos de Pacini/efectos de los fármacos , Corpúsculos de Pacini/patología , Pénfigo/epidemiología , Pénfigo/inmunología , Pénfigo/patología , Pénfigo/fisiopatología , Postura , Piel/efectos de los fármacos , Piel/metabolismoRESUMEN
Pathology of chronic Chagas' disease involves peripheral nervous system (PNS) compromise. A high prevalence of antibodies reacting with nervous system antigens has been found in the sera of patients and infected animals, although their physiological role in mediating PNS tissue damage is unknown. Here, we demonstrate that epineural injection of sera from Trypanosoma cruzi infected mice affects the characteristics of the sciatic nerve action potential (SNAP) depending on the parasite strain. Sera from mice infected with the reticulotropic/neurotropic RA strain with reactivity against sciatic nerve (RA/Ne+ sera) induced delays on latency and diminished amplitudes 4 days after injection. Sera from mice infected with the myotropic CA-I strain failed to affect SNAP. Purified immunoglobulin (Ig)G from RA/Ne+ also diminished the amplitude of SNAP. Deposits of IgG labelling axonal fibres and/or myelin sheaths were detected in nerves injected with RA/Ne+ sera. No major histological damage or parasite DNA was found in those nerves. The SNAP changes after sera injection were similar to those observed in mice injected with trypomastigotes in the epineurum 17 days before and in chronically infected animals. This investigation suggests that autoantibodies triggered as a consequence of T. cruzi infection are able to mediate, at least in part, the electrophysiological abnormalities observed in PNS during the course of Chagas' disease.