RESUMEN
Lyme neuroborreliosis (LNB) is a complex neuroinflammatory disorder caused by Borrelia burgdorferi, which is transmitted through tick bites. Epigenetic alterations, specifically DNA methylation (DNAm), could play a role in the host immune response during infection. In this study, we present the first genome-wide analysis of DNAm in peripheral blood mononuclear cells from patients with LNB and those without LNB. Using a network-based approach, we highlighted HLA genes at the core of these DNAm changes, which were found to be enriched in immune-related pathways. These findings shed light on the role of epigenetic modifications in the LNB pathogenesis that should be confirmed and further expanded upon in future studies.
Asunto(s)
Borrelia burgdorferi , Neuroborreliosis de Lyme , Humanos , Neuroborreliosis de Lyme/genética , Metilación de ADN , Leucocitos Mononucleares , Borrelia burgdorferi/genéticaRESUMEN
Lyme neuroborreliosis (LNB) in Europe may manifest with painful meningoradiculoneuritis (also known as Bannwarth syndrome) or lymphocytic meningitis with or without cranial neuritis (peripheral facial palsy). We assessed host immune responses and the prevalence of TLR1 (toll-like receptor 1)-1805GG polymorphism to gain insights into the pathophysiology of these conditions. Regardless of LNB manifestation, most mediators associated with innate and adaptive immune responses were concentrated in cerebrospinal fluid; serum levels were unremarkable. When stratified by specific clinical manifestation, patients with meningoradiculoneuritis had higher levels of B-cell chemoattractants CXC motif chemokine ligand (CXCL) 12 and CXCL13 and T-cell-associated mediators CXCL9, CXCL10, and interleukin 17, compared with those without radicular pain. Moreover, these patients had a higher frequency of TLR1-1805GG polymorphism and more constitutional symptoms. These findings demonstrate that meningoradiculoneuritis is a distinct clinical entity with unique immune and genetic pathophysiology, providing new considerations for the study of LNB and borrelial meningoradiculitis.
Asunto(s)
Borrelia , Citocinas , Parálisis Facial , Neuroborreliosis de Lyme , Quimiocinas/metabolismo , Citocinas/metabolismo , Europa (Continente) , Humanos , Neuroborreliosis de Lyme/líquido cefalorraquídeo , Neuroborreliosis de Lyme/diagnóstico , Neuroborreliosis de Lyme/genética , PrevalenciaRESUMEN
The pathophysiology of post-treatment Lyme disease syndrome (PTLDS) may be linked to overactive immunity including aberrant activity of the brain's resident immune cells, microglia. Here we used [11C]DPA-713 and positron emission tomography to quantify the 18 kDa translocator protein, a marker of activated microglia or reactive astrocytes, in the brains of patients with post-treatment Lyme disease symptoms of any duration compared to healthy controls. Genotyping for the TSPO rs6971 polymorphism was completed, and individuals with the rare, low affinity binding genotype were excluded. Data from eight brain regions demonstrated higher [11C]DPA-713 binding in 12 patients relative to 19 controls. [11C]DPA-713 PET is a promising tool to study cerebral glial activation in PTLDS and its link to cognitive symptoms.
Asunto(s)
Acetamidas/farmacocinética , Encéfalo/diagnóstico por imagen , Neuroborreliosis de Lyme/diagnóstico por imagen , Tomografía de Emisión de Positrones , Pirazoles/farmacocinética , Pirimidinas/farmacocinética , Adolescente , Adulto , Anciano , Proteínas Reguladoras de la Apoptosis/genética , Encéfalo/efectos de los fármacos , Radioisótopos de Carbono/farmacocinética , Trastornos del Conocimiento/diagnóstico por imagen , Trastornos del Conocimiento/etiología , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Neuroborreliosis de Lyme/genética , Imagen por Resonancia Magnética , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Pruebas Neuropsicológicas , Proyectos Piloto , Polimorfismo Genético/genética , Índice de Severidad de la Enfermedad , Adulto JovenAsunto(s)
Antígenos Bacterianos/genética , Proteínas Bacterianas/genética , Grupo Borrelia Burgdorferi/genética , Lipoproteínas/genética , Neuroborreliosis de Lyme/genética , Variación Antigénica/genética , Antígenos Bacterianos/inmunología , Proteínas Bacterianas/inmunología , Southern Blotting , Western Blotting , Grupo Borrelia Burgdorferi/inmunología , Técnicas de Cocultivo , ADN Bacteriano/química , ADN Bacteriano/genética , Electroforesis en Gel de Campo Pulsado , Células HL-60 , Humanos , Lipoproteínas/inmunología , Neuroborreliosis de Lyme/sangre , Neuroborreliosis de Lyme/inmunología , Neuroborreliosis de Lyme/patologíaRESUMEN
The cause, or causes, of the vast majority of Alzheimer's disease cases are unknown. A number of contributing factors have been postulated, including infection. It has long been known that the spirochete Treponema pallidum, which is the infective agent for syphilis, can in its late stages cause dementia, chronic inflammation, cortical atrophy and amyloid deposition. Spirochetes of unidentified types and strains have previously been observed in the blood, CSF and brain of 14 AD patients tested and absent in 13 controls. In three of these AD cases spirochetes were grown in a medium selective for Borrelia burgdorferi. In the present study, the phylogenetic analysis of these spirochetes was made. Positive identification of the agent as Borrelia burgdorferi sensu stricto was based on genetic and molecular analyses. Borrelia antigens and genes were co-localized with beta-amyloid deposits in these AD cases. The data indicate that Borrelia burgdorferi may persist in the brain and be associated with amyloid plaques in AD. They suggest that these spirochetes, perhaps in an analogous fashion to Treponema pallidum, may contribute to dementia, cortical atrophy and amyloid deposition. Further in vitro and in vivo studies may bring more insight into the potential role of spirochetes in AD.
Asunto(s)
Enfermedad de Alzheimer/microbiología , Enfermedad de Alzheimer/patología , Borrelia burgdorferi/aislamiento & purificación , Encéfalo/microbiología , Encéfalo/patología , Neuroborreliosis de Lyme/complicaciones , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/genética , Atrofia/inmunología , Atrofia/patología , Secuencia de Bases , Western Blotting , Borrelia burgdorferi/genética , Corteza Cerebral/patología , Enfermedad Crónica , Cartilla de ADN/genética , Lóbulo Frontal/microbiología , Lóbulo Frontal/patología , Genotipo , Humanos , Hibridación in Situ , Neuroborreliosis de Lyme/genética , Reacción en Cadena de la Polimerasa , ARN Ribosómico 16S/análisis , ARN Ribosómico 16S/genética , Spirochaetales/genéticaAsunto(s)
Borrelia burgdorferi/metabolismo , Enfermedad de Lyme/complicaciones , Neuroborreliosis de Lyme/complicaciones , Trastornos de la Motilidad Ocular/etiología , Adulto , Borrelia burgdorferi/genética , Diagnóstico Diferencial , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Enfermedad de Lyme/genética , Enfermedad de Lyme/metabolismo , Neuroborreliosis de Lyme/genética , Neuroborreliosis de Lyme/metabolismo , Masculino , Reacción en Cadena de la PolimerasaRESUMEN
Elucidating the cellular immune response to infectious agents is a prerequisite for understanding disease pathogenesis and designing effective vaccines. In the identification of microbial T-cell epitopes, the availability of purified or recombinant bacterial proteins has been a chief limiting factor. In chronic infectious diseases such as Lyme disease, immune-mediated damage may add to the effects of direct infection by means of molecular mimicry to tissue autoantigens. Here, we describe a new method to effectively identify both microbial epitopes and candidate autoantigens. The approach combines data acquisition by positional scanning peptide combinatorial libraries and biometric data analysis by generation of scoring matrices. In a patient with chronic neuroborreliosis, we show that this strategy leads to the identification of potentially relevant T-cell targets derived from both Borrelia burgdorferi and the host. We also found that the antigen specificity of a single T-cell clone can be degenerate and yet the clone can preferentially recognize different peptides derived from the same organism, thus demonstrating that flexibility in T-cell recognition does not preclude specificity. This approach has potential applications in the identification of ligands in infectious diseases, tumors and autoimmune diseases.