RESUMO
Anti-CD20 therapy to deplete B cells is highly efficacious in preventing new white matter lesions in patients with relapsing-remitting multiple sclerosis (RRMS), but its protective capacity against gray matter injury and axonal damage is unclear. In a passive experimental autoimmune encephalomyelitis (EAE) model whereby TH17 cells promote brain leptomeningeal immune cell aggregates, we found that anti-CD20 treatment effectively spared myelin content and prevented myeloid cell activation, oxidative damage, and mitochondrial stress in the subpial gray matter. Anti-CD20 treatment increased B cell survival factor (BAFF) in the serum, cerebrospinal fluid, and leptomeninges of mice with EAE. Although anti-CD20 prevented gray matter demyelination, axonal loss, and neuronal atrophy, co-treatment with anti-BAFF abrogated these benefits. Consistent with the murine studies, we observed that elevated BAFF concentrations after anti-CD20 treatment in patients with RRMS were associated with better clinical outcomes. Moreover, BAFF promoted survival of human neurons in vitro. Together, our data demonstrate that BAFF exerts beneficial functions in MS and EAE in the context of anti-CD20 treatment.
Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla Recidivante-Remitente , Humanos , Animais , Camundongos , Neuroproteção , Encéfalo , Substância Cinzenta , Apresentação de Antígeno , Atrofia , Encefalomielite Autoimune Experimental/tratamento farmacológicoRESUMO
A better understanding of the pathological mechanisms that drive neurodegeneration in people living with multiple sclerosis (MS) is needed to design effective therapies to treat and/or prevent disease progression. We propose that CNS-intrinsic inflammation and re-modelling of the sub-arachnoid space of the leptomeninges sets the stage for neurodegeneration from the earliest stages of MS. While neurodegenerative processes are clinically silent early in disease, ageing results in neurodegenerative changes that become clinically manifest as progressive disability. Here we review pathological correlates of MS disease progression, highlight emerging mouse models that mimic key progressive changes in MS, and provide new perspectives on therapeutic approaches to protect against MS-associated neurodegeneration.
Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Camundongos , Animais , Humanos , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/terapia , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/patologia , Progressão da Doença , Inflamação/patologia , Modelos Animais de DoençasRESUMO
People living with multiple sclerosis (MS) experience episodic CNS white matter lesions instigated by autoreactive T cells. With age, patients with MS show evidence of gray matter demyelination and experience devastating nonremitting symptomology. What drives progression is unclear and studying this has been hampered by the lack of suitable animal models. Here, we show that passive experimental autoimmune encephalomyelitis (EAE) induced by an adoptive transfer of young Th17 cells induced a nonremitting clinical phenotype that was associated with persistent leptomeningeal inflammation and cortical pathology in old, but not young, SJL/J mice. Although the quantity and quality of T cells did not differ in the brains of old versus young EAE mice, an increase in neutrophils and a decrease in B cells were observed in the brains of old mice. Neutrophils were also found in the leptomeninges of a subset of progressive MS patient brains that showed evidence of leptomeningeal inflammation and subpial cortical demyelination. Taken together, our data show that while Th17 cells initiate CNS inflammation, subsequent clinical symptoms and gray matter pathology are dictated by age and associated with other immune cells, such as neutrophils.
Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Animais , Substância Cinzenta/patologia , Humanos , Inflamação , Camundongos , Neutrófilos/patologiaRESUMO
Although SARS-CoV-2 infects the upper respiratory tract, we know little about the amount, type, and kinetics of antibodies (Ab) generated in the oral cavity in response to COVID-19 vaccination. We collected serum and saliva samples from participants receiving two doses of mRNA COVID-19 vaccines and measured the level of anti-SARS-CoV-2 Ab. We detected anti-Spike and anti-Receptor Binding Domain (RBD) IgG and IgA, as well as anti-Spike/RBD associated secretory component in the saliva of most participants after dose 1. Administration of a second dose of mRNA boosted the IgG but not the IgA response, with only 30% of participants remaining positive for IgA at this timepoint. At 6 months post-dose 2, these participants exhibited diminished anti-Spike/RBD IgG levels, although secretory component-associated anti-Spike Ab were more stable. Examining two prospective cohorts we found that participants who experienced breakthrough infections with SARS-CoV-2 variants had lower levels of vaccine-induced serum anti-Spike/RBD IgA at 2-4 weeks post-dose 2 compared to participants who did not experience an infection, whereas IgG levels were comparable between groups. These data suggest that COVID-19 vaccines that elicit a durable IgA response may have utility in preventing infection. Our study finds that a local secretory component-associated IgA response is induced by COVID-19 mRNA vaccination that persists in some, but not all participants. The serum and saliva IgA response modestly correlate at 2-4 weeks post-dose 2. Of note, levels of anti-Spike serum IgA (but not IgG) at this timepoint are lower in participants who subsequently become infected with SARS-CoV-2. As new surges of SARS-CoV-2 variants arise, developing COVID-19 booster shots that provoke high levels of IgA has the potential to reduce person-to-person transmission.
Assuntos
COVID-19 , Vacinas Virais , Anticorpos Antivirais , COVID-19/prevenção & controle , Vacinas contra COVID-19 , Humanos , Estudos Prospectivos , RNA Mensageiro/genética , SARS-CoV-2 , Componente Secretório , VacinaçãoRESUMO
The CNS is tightly regulated to maintain immune surveillance and efficiently respond to injury and infections. The current appreciation that specialized "brain-adjacent" regions in the CNS are in fact not immune privileged during the steady state, and that immune cells can take up residence in more immune-privileged areas of the CNS during inflammation with consequences on the adjacent brain parenchyma, beg the question of what cell types support CNS immunity. As they do in secondary lymphoid organs, we provide evidence in this review that stromal cells also underpin brain-resident immune cells. We review the organization and function of stromal cells in different anatomical compartments of the CNS and discuss their capacity to rapidly establish and elaborate an immune-competent niche that further sustains immune cells entering the CNS from the periphery. In summary, we argue that stromal cells are key cellular agents that support CNS-compartmentalized immunity.
Assuntos
Encéfalo/imunologia , Sistema Nervoso Central/imunologia , Células Estromais/fisiologia , Animais , Compartimento Celular , Microambiente Celular , Humanos , Imunidade Celular , Vigilância ImunológicaRESUMO
While the antibody response to SARS-CoV-2 has been extensively studied in blood, relatively little is known about the antibody response in saliva and its relationship to systemic antibody levels. Here, we profiled by enzyme-linked immunosorbent assays (ELISAs) IgG, IgA and IgM responses to the SARS-CoV-2 spike protein (full length trimer) and its receptor-binding domain (RBD) in serum and saliva of acute and convalescent patients with laboratory-diagnosed COVID-19 ranging from 3-115 days post-symptom onset (PSO), compared to negative controls. Anti-SARS-CoV-2 antibody responses were readily detected in serum and saliva, with peak IgG levels attained by 16-30 days PSO. Longitudinal analysis revealed that anti-SARS-CoV-2 IgA and IgM antibodies rapidly decayed, while IgG antibodies remained relatively stable up to 105 days PSO in both biofluids. Lastly, IgG, IgM and to a lesser extent IgA responses to spike and RBD in the serum positively correlated with matched saliva samples. This study confirms that serum and saliva IgG antibodies to SARS-CoV-2 are maintained in the majority of COVID-19 patients for at least 3 months PSO. IgG responses in saliva may serve as a surrogate measure of systemic immunity to SARS-CoV-2 based on their correlation with serum IgG responses.