RESUMEN
OBJECTIVES: This study aimed to evaluate whether switching disease-modifying therapies (DMTs) from sphingosine-1 phosphate (S1P) receptor modulators to either natalizumab (NTZ) or dimethyl fumarate (DMF) could restore the effectiveness of SARS-CoV-2 mRNA vaccination in patients with multiple sclerosis (MS). METHODS: This study included 9 controls and 33 patients with MS: 7 patients treated with DMF, 7 patients treated with NTZ, 9 patients treated with S1P receptor modulators, and 10 patients who had switched DMTs from S1P receptor modulators to DMF or NTZ by the second vaccine dose. The patients who had switched DMTs were classified into two groups, based on whether their lymphocyte counts were above or below 1000/µL at the time of vaccination. In addition, relapses within 6 months after switching DMTs were also evaluated in these patients. Six months after the second dose of the vaccination, anti-SARS-CoV-2 spike antibodies were evaluated in all participants, and spike specific CD4+ T cells were also assessed in patients who had switched DMTs from S1P receptor modulators. RESULTS: Patients treated with S1P receptor modulators had lower levels of anti-SARS-CoV-2 spike antibodies than the controls and patients treated with DMF and NTZ. On the other hand, in patients who had switched DMTs from S1P receptor modulators, a recovery of lymphocyte counts above 1000/µL resulted in restored humoral and cellular immune responses to the vaccination. There were no neurological relapses in patients who had switched DMTs from S1P receptor modulators to NTZ. CONCLUSION: SARS-CoV-2 mRNA vaccination is expected to be effective in patients whose lymphocyte counts have recovered due to switching DMTs from S1P receptor modulators. Switching DMTs from S1P receptor modulators to NTZ before vaccination may be beneficial in achieving efficacy for SARS-CoV-2 mRNA vaccination, with a reduced risk of relapse.
Asunto(s)
COVID-19 , Dimetilfumarato , Esclerosis Múltiple , Natalizumab , SARS-CoV-2 , Humanos , Femenino , Dimetilfumarato/uso terapéutico , Masculino , Adulto , Natalizumab/uso terapéutico , Persona de Mediana Edad , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/tratamiento farmacológico , COVID-19/prevención & control , COVID-19/inmunología , SARS-CoV-2/inmunología , Moduladores de los Receptores de fosfatos y esfingosina 1/uso terapéutico , Moduladores de los Receptores de fosfatos y esfingosina 1/farmacología , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/uso terapéutico , Inmunosupresores/uso terapéutico , Vacunación/métodos , Sustitución de Medicamentos , Anticuerpos Antivirales/sangreRESUMEN
Myasthenia gravis (MG) is a neurological disease caused by autoantibodies against neuromuscular-associated proteins. While MG frequently develops in thymoma patients, the etiologic factors for MG are not well understood. Here, by constructing a comprehensive atlas of thymoma using bulk and single-cell RNA-sequencing, we identify ectopic expression of neuromuscular molecules in MG-type thymoma. These molecules are found within a distinct subpopulation of medullary thymic epithelial cells (mTECs), which we name neuromuscular mTECs (nmTECs). MG-thymoma also exhibits microenvironments dedicated to autoantibody production, including ectopic germinal center formation, T follicular helper cell accumulation, and type 2 conventional dendritic cell migration. Cell-cell interaction analysis also predicts the interaction between nmTECs and T/B cells via CXCL12-CXCR4. The enrichment of nmTECs presenting neuromuscular molecules within MG-thymoma is further confirmed immunohistochemically and by cellular composition estimation from the MG-thymoma transcriptome. Altogether, this study suggests that nmTECs have a significant function in MG pathogenesis via ectopic expression of neuromuscular molecules.
Asunto(s)
Miastenia Gravis , Timoma , Neoplasias del Timo , Células Epiteliales/patología , Expresión Génica , Humanos , Miastenia Gravis/genética , Timoma/genética , Neoplasias del Timo/genética , Microambiente TumoralRESUMEN
BACKGROUND AND OBJECTIVES: Recently accumulating evidence suggests the pivotal role of type 1 interferon (IFN-1) signature in the pathogenesis of neuromyelitis optica spectrum disorder (NMOSD). However, the mechanism of the initial trigger that augments IFN-1 pathway in the peripheral immune system of NMOSD has yet to be elucidated. METHODS: Clinical samples were obtained from 32 patients with aquaporin-4 antibody-positive NMOSD and 23 healthy subjects. IFN-1 induction in peripheral blood mononuclear cells (PBMCs) by serum-derived cell-free DNA (cfDNA) was assessed in combination with blockades of DNA sensors in vitro. CfDNA fraction was analyzed for DNA methylation profiles by bisulfite sequencing, elucidating the cellular origin of cfDNA. The induction of neutrophil extracellular trap related cell death (NETosis) was further analyzed in NMOSD and control groups, and the efficacy of pharmacologic intervention of NETosis was assessed. RESULTS: Enhanced IFN-1 induction by cfDNA derived from NMOSD was observed in PBMCs with cofactor of LL37 antimicrobial peptide. DNase treatment, cGAS inhibitor, and Toll-like receptor 9 antagonist efficiently inhibited IFN-1 production. DNA methylation pattern of cfDNA in patients with NMOSD demonstrated that the predominant cellular source of cfDNA was neutrophils. Whole blood transcriptome analysis also revealed neutrophil activation in NMOSD. In addition, enhanced NETosis induction was observed with NMOSD-derived sera, and efficient pharmacologic inhibition of NETosis with dipyridamole was observed. DISCUSSION: Our study highlights the previously unrevealed role of cfDNA predominantly released by neutrophil in the induction of IFN-1 signature in NMOSD and further indicate a novel pharmacologic target in NMOSD.
Asunto(s)
Ácidos Nucleicos Libres de Células , Neuromielitis Óptica , Humanos , Interferones , Leucocitos Mononucleares , Neutrófilos/patologíaRESUMEN
Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing autoimmune disease characterized by the presence of pathogenic autoantibodies, anti-aquaporin 4 (AQP4) antibodies. Recently, HLA-DQA1*05:03 was shown to be significantly associated with NMOSD in a Japanese patient cohort. However, the specific mechanism by which HLA-DQA1*05:03 is associated with the development of NMOSD has yet to be elucidated. In the current study, we revealed that HLA-DQA1*05:03 exhibited significantly higher cell surface expression levels compared to other various DQA1 alleles, and that its expression strongly depended on the amino acid sequence of the α1 domain, with a preference for leucine at position 75. Moreover, in silico analysis indicated that the HLA-DQ encoded by HLA-DQA1*05:03 preferentially presents immunodominant AQP4 peptides, and that the peptide major histocompatibility complexes (pMHCs) are more energetically stable in the presence of HLA-DQA1*05:03 than other HLA-DQA1 alleles. In silico 3D structural models were also applied to investigate the validity of the energetic stability of pMHCs. Taken together, our findings indicate that HLA-DQA1*05:03 possesses a distinct property to play a pathogenic role in the development of NMOSD.
Asunto(s)
Acuaporina 4/metabolismo , Membrana Celular/metabolismo , Cadenas alfa de HLA-DQ/metabolismo , Epítopos Inmunodominantes , Neuromielitis Óptica/metabolismo , Secuencia de Aminoácidos , Acuaporina 4/inmunología , Autoanticuerpos/sangre , Membrana Celular/inmunología , Células HEK293 , Cadenas alfa de HLA-DQ/genética , Cadenas alfa de HLA-DQ/inmunología , Humanos , Inmunoglobulina G/sangre , Modelos Moleculares , Neuromielitis Óptica/diagnóstico , Neuromielitis Óptica/genética , Neuromielitis Óptica/inmunología , Unión Proteica , Dominios ProteicosRESUMEN
BACKGROUND: Intractable neuropathic pain is a common symptom of neuromyelitis optica spectrum disorder (NMOSD). However, the underlying mechanism of NMOSD pain remains to be elucidated. In this study, we focused on ATP, which is one of the damage-associated molecular patterns, and also a well-recognized molecule involved in peripheral neuropathic pain. METHODS: We assessed the development of pain symptoms by injecting anti-AQP4 recombinant autoantibodies (rAQP4 IgG) into rat spinal cords. We incubated HEK293 cells expressing AQP4 (HEK-AQP4) and rat astrocytes with rAQP4 IgG and assessed the level of ATP in the supernatant. We performed transcriptome analysis of the spinal cords injected with rAQP4 IgG. Pharmacological inhibition was also applied to investigate the involvement of ATP in the development of neuropathic pain in our rat model. The ATP concentration within the cerebrospinal fluid was examined in patients with NMOSD and other neurological diseases. RESULTS: Development of mechanical allodynia was confirmed in rAQP4 IgG-treated rats. AQP4-Ab-mediated extracellular ATP release from astrocytes was observed in vitro, and pharmacological inhibition of ATP receptor reversed mechanical allodynia in the rAQP4 IgG-treated rats. Furthermore, transcriptome analysis revealed elevation of gene expressions related to several ATP receptors including P2rx4 and IL1B in the spinal cord of rAQP4 IgG-treated rats. In patients, CSF ATP concentration was significantly higher in the acute and remission phase of NMOSD than in multiple sclerosis or other neurological disorders. CONCLUSION: Anti-AQP4 antibody was shown to induce the release of extracellular ATP from astrocytes. The ATP-mediated development of mechanical allodynia was also suggested in rats treated with anti-AQP4 antibody. Our study indicates the pivotal role of ATP in the pain mechanism of NMOSD.
Asunto(s)
Adenosina Trifosfato/metabolismo , Acuaporina 4/inmunología , Astrocitos/inmunología , Autoanticuerpos/farmacología , Neuralgia/inmunología , Neuromielitis Óptica/inmunología , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Células HEK293 , Humanos , Neuralgia/metabolismo , Neuromielitis Óptica/metabolismo , RatasRESUMEN
Sjögren's syndrome is an autoimmune disease characterized by chronic sialadenitis and keratoconjunctivitis sicca. While dryness of the salivary and lacrimal glands is a core symptom, neurological complications are known to occur as part of a variety of extraglandular manifestations. The reported frequency of neurological complications ranges from 1.8% to 60%, with a wide variety of central, peripheral, and muscular manifestations. In 25% of cases, neurological symptoms precede the diagnosis of Sjögren's syndrome. Therefore, in the presence of unexplained neurological symptoms, it is important to exclude Sjogren's syndrome.
Asunto(s)
Síndrome de Sjögren , Humanos , Síndrome de Sjögren/diagnósticoRESUMEN
Although recent studies indicate the involvement of monocytes in accelerating the lesion formation of neuromyelitis optica spectrum disorder (NMOSD), the precise mechanism of the innate immune system activation remains elusive. Thus, in this study, we aimed to clarify the mechanisms of NMOSD pathogenesis from the viewpoint of innate immunity activation. We established anti-AQP4 recombinant autoantibodies (Ab) from plasmablasts in NMOSD patient's CSF. Human astrocytes treated with anti-AQP4 Ab produced a significant amount of CCL2 and contributed to the efficient recruitment of monocytes. Moreover, mitochondrial DNA (mtDNA), which activated monocytes via Toll-like receptor 9 (TLR9), was released from astrocytes treated with anti-AQP4 Ab. MtDNA further enhanced CCL2 production by monocytes, and it was demonstrated that mtDNA concentration correlated with the efficiency of monocyte recruitment in the CSF of NMOSD patients. In conclusion, these observations highlight that mtDNA which was released from astrocytes damaged by anti-AQP4 Ab has a central role in establishing the inflammatory loop of monocyte recruitment and activation via an innate immunity pathway.
Asunto(s)
Acuaporina 4/inmunología , ADN Mitocondrial/genética , Mitocondrias/genética , Monocitos/inmunología , Neuromielitis Óptica/genética , Adulto , Anciano , Anticuerpos/farmacología , Astrocitos/efectos de los fármacos , Astrocitos/inmunología , Quimiocina CCL2/metabolismo , Femenino , Células HEK293 , Humanos , Inmunidad Innata , Persona de Mediana Edad , Monocitos/efectos de los fármacos , Neuromielitis Óptica/inmunología , Receptor Toll-Like 9/metabolismoRESUMEN
AIM: To study the influence of exercise on the QOL of local elderly individuals, we created an activity scale for the elderly (ASE) and investigated its reliability and validity. METHODS: We created 36-item ASE and performed factor analysis. The reliability of the ASE was tested by determining Cronbach's coefficient alpha and confirmatory factor analysis in a cohort of 5,280 people, living in the community. The validity of the ASE was assessed by analyzing the interrelationship between the subdomains, age, and exercise. RESULTS: By factor analysis, four subdomains and 20 items remained significant for measuring ASE. The average ASE in the 5,280 people was 27.18+/-5.28 points, with no sex difference. Confirmatory factor analysis showed the stability of the four subdomains. Cronbach's alpha demonstrated the internal consistency of the scale. Regarding the relationship between the four subdomains, age, and exercise, a significant difference was found between those who exercised and those who did not exercise, and between the 4 different age groups. By means of two-way ANOVA, significant interaction was found between exercise and age; ASE decreased from 26.3 points in the sixth decade of life to 23.9 in the seventh decade of life in those who did not exercise, while no decrease was found in those who exercised. Furthermore, ASE was significantly higher in those who exercised than those who did not non-exercise in each age decade group. These results suggest that exercise prevents age-associated decline in ASE. CONCLUSION: ASE provides a reliable and valid measure for the QOL of elderly individuals living in the community, and exercise appears beneficial for preventing age-associated decline in ASE.