A wide spectrum of clinical manifestations has become a hallmark of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) COVID-19 pandemic, although the immunological underpinnings of diverse disease outcomes remain to be defined. We performed detailed characterization of B cell responses through high-dimensional flow cytometry to reveal substantial heterogeneity in both effector and immature populations. More notably, critically ill patients displayed hallmarks of extrafollicular B cell activation and shared B cell repertoire features previously described in autoimmune settings. Extrafollicular activation correlated strongly with large antibody-secreting cell expansion and early production of high concentrations of SARS-CoV-2-specific neutralizing antibodies. Yet, these patients had severe disease with elevated inflammatory biomarkers, multiorgan failure and death. Overall, these findings strongly suggest a pathogenic role for immune activation in subsets of patients with COVID-19. Our study provides further evidence that targeted immunomodulatory therapy may be beneficial in specific patient subpopulations and can be informed by careful immune profiling.

BackgroundAfrican Americans have been reported to have a higher prevalence of Alzheimer’s disease (AD) than Caucasians, but etiology-specific AD biomarkers have not been systematically analyzed in older African Americans. Coexisting cerebrovascular disease may also contribute to this increased prevalence. We hypothesized that cerebrospinal fluid (CSF) biomarkers of amyloid, neurodegeneration, and endothelial dysfunction would differ between older African Americans and Caucasians with normal cognition and cognitive impairment associated with AD.MethodsWe prospectively recruited 135 older Americans to undergo detailed clinical, neuropsychological, genetic, magnetic resonance imaging (MRI), and CSF analysis from 2013 to 2015 at Emory University (Atlanta, GA, USA). We compared levels of CSF markers for β-amyloid (Aβ42, Aβ40), total and phosphorylated tau (t-tau and p-tau181, respectively), endothelial dysfunction (soluble vascular cell adhesion molecule 1, soluble intercellular adhesion molecule 1), α-synuclein, and neurodegeneration (neurofilament light chain [NfL]), as well as MRI markers, for hippocampal atrophy and cerebrovascular disease (white matter hyperintensity [WMH] volume).ResultsSixty-five older African Americans (average age, 69.1 years) and 70 older Caucasians (average age, 70.8 years) were included. After adjusting for demographic variables, AD risk alleles, and cognitive function, older African Americans had lower CSF levels of p-tau181 (difference of 7.4 pg/ml; 95% CI, 3.7–11.2 pg/ml; p < 0.001), t-tau (difference of 23.6 pg/ml; 95% CI, 9.5–37.7; p = 0.001), and Aβ40 (difference of 1.35 ng/ml; 95% CI, 0.29–2.42 ng/ml; p = 0.013) despite similar levels of Aβ42, NfL, WMH volume, and hippocampal volume. Cognitively impaired African Americans also had lower CSF t-tau/Aβ42 (difference of 0.255 per 1-SD change in composite cognition; 95% CI, 0.100–0.409; p = 0.001) and p-tau181/Aβ42 (difference of 0.076 per 1-SD change in composite cognition; 95% CI, 0.031–0.122; p = 0.001). These could not be explained by measured biomarkers of non-AD processes, but African Americans may be more susceptible than Caucasians to the cognitive effects of WMH.ConclusionsDespite comparable levels of CSF Aβ42 and Aβ42/Aβ40, cognitive impairment in African Americans is associated with smaller changes in CSF tau markers but greater impact from similar WMH burden than Caucasians. Race-associated differences in CSF tau markers and ratios may lead to underdiagnosis of AD in African Americans.Trial registrationClinicalTrials.gov, NCT02089555. Retrospectively registered on 14 March 2014.

T he pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to >1.5 million infections in the United States (30% of global cases) and >90,000 deaths as of May 20, 2020 (1). Coronavirus disease (COVID-19, the clinical syndrome associated with SARS-Cov-2) is most commonly characterized by respiratory illness and viral pneumonia with fever, cough, and shortness of breath, and progression to acute respiratory distress syndrome in severe cases (2). Although neurologic complications have been noted in previous human coronavirus infections (3-5), there are few in-depth investigations for neurologic syndromes associated with SARS-CoV-2 infection (6). This deficiency can result from the need to reduce unnecessary staff exposure and difficulties in establishing preillness neurologic status without regular family visitors. It is known that neurons and glia express the putative SARS-CoV-2 receptor angiotensin converting enzyme 2 (7), and that the related coronavirus SARS-CoV (responsible for the 2003 SARS outbreak) can inoculate the mouse olfactory bulb (8). If SARS-CoV-2 can enter the central nervous system (CNS) directly or through hematogenous spread, cerebrospinal fluid (CSF) changes, including viral RNA, IgM, or cytokine levels, might support CNS infection as a cause for neurologic symptoms. We report clinical, blood, neuroimaging, and CSF findings for 3 patients with laboratory-confirmed COVID-19 and a range of neurologic outcomes (neuro-COVID). We also show the presence of SARS-CoV-2 antibodies in the blood and CSF of these patients, consistent with CNS penetration of disease. Methods We describe the clinical, laboratory and radiologic findings for 3 patients with respiratory failure and neurologic complications caused by COVID-19. This case series was reviewed and exempted from Emory Institutional Review Board approval. Medical records were reviewed by 4 of the coauthors (K.B., A.A., M.E.M., and W.T.H.). CSF Serologic Analysis, Cytokines, and Molecular Testing We assessed CSF IgM by using an in-house ELISA against SARS-CoV-2 S1 or envelope (E) protein. This ELISA was modified from an in-house blood-based Encephalopathy and Encephalitis Associated with Cerebrospinal Fluid Cytokine Alterations and Coronavirus Disease,

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A wide clinical spectrum has become a hallmark of the SARS-CoV-2 (COVID-19) pandemic, although its immunologic underpinnings remain to be defined. We have performed deep characterization of B cell responses through high-dimensional flow cytometry to reveal substantial heterogeneity in both effector and immature populations. More notably, critically ill patients displayed hallmarks of extrafollicular B cell activation as previously described in autoimmune settings. Extrafollicular activation correlated strongly with large antibody secreting cell expansion and early production of high levels of SARS-CoV-2-specific antibodies. Yet, these patients fared poorly with elevated inflammatory biomarkers, multi-organ failure, and death. Combined, the findings strongly indicate a major pathogenic role for immune activation in subsets of COVID-19 patients. Our study suggests that, as in autoimmunity, targeted immunomodulatory therapy may be beneficial in specific patient subpopulations that can be identified by careful immune profiling.

Inflammation is a common process involved in aging, multiple sclerosis (MS), and age-related neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD), but there is limited evidence for the effects of aging on inflammation in the central nervous system. We collected cerebrospinal fluid (CSF) from 105 healthy control subjects representing a wide age range (23–86), and analyzed levels of cytokines associated innate immunity (TNF-α) and different T-helper subtypes: interferon–gamma induced protein 10 (IP-10) for Th1, interleukin-10 (IL-10) for Th2, and interleukin 8 (IL-8/CXCL8) for Th17. We show that CSF levels of TNF-α, IP-10, and IL-8 all increased linearly with age, but levels of IL-10 demonstrated a U-shaped relationship with age. We further found greater age-related increases in TNF-α, IL-10, and IL-8 relative to increases in IP-10 levels, consistent with a shift from Th1 to other inflammatory phenotypes. Finally, when we analyzed the same four cytokines in people with neurological disorders, we found that MS and AD, but not PD or dementia with Lewy bodies, further accentuated the age-related shift from Th1- to non-Th1-related cytokines. We propose that CSF cytokine levels represent powerful surrogates of brain inflammation and aging, and some, but not all, neurological disorders accelerate the shift away from Th1 phenotypes.

BackgroundOxidative injury to retinal pigment epithelium (RPE) and retinal photoreceptors has been linked to a number of retinal diseases, including age-related macular degeneration (AMD). Reactive oxygen species (ROS)-mediated gene expression has been extensively studied at transcriptional levels. Also, the post-transcriptional control of gene expression at the level of translational regulation has been recently reported. However, the microRNA (miRNA/miR)-mediated post-transcriptional regulation in human RPE cells has not been thoroughly looked at. Increasing evidence points to a potential role of miRNAs in diverse physiological processes.Methodology/Principal FindingsWe demonstrated for the first time in a human retinal pigment epithelial cell line (ARPE-19) that the post-transcriptional control of gene expression via miRNA modulation regulates human catalase, an important and potent component of cell's antioxidant defensive network, which detoxifies hydrogen peroxide (H2O2) radicals. Exposure to several stress-inducing agents including H2O2 has been reported to alter miRNA expression profile. Here, we demonstrated that a sublethal dose of H2O2 (200 µM) up-regulated the expression of miR-30b, a member of the miR-30 family, which inhibited the expression of endogenous catalase both at the transcript and protein levels. However, antisense (antagomirs) of miR-30b was not only found to suppress the miR-30b mimics-mediated inhibitions, but also to dramatically increase the expression of catalase even under an oxidant environment.Conclusions/SignificanceWe propose that a microRNA antisense approach could enhance cytoprotective mechanisms against oxidative stress by increasing the antioxidant defense system.

African Americans are under-represented in Alzheimer’s disease (AD)-related biomarker studies, and it has been speculated that mistrust plays a major factor in the recruitment of African Americans for studies involving invasive procedures such as the lumbar puncture (LP). We set out to determine factors associated with non-participation in a biomarker study aiming to explore cerebrospinal fluid (CSF) AD biomarker differences between older African Americans and Caucasians. We also surveyed participants’ procedure-related perception (a standard medical procedure vs. a frightening invasive procedure) and reluctance, as well as the rate and type of post-procedure discomfort and complications. Among 288 subjects approached for study participation, 145 (50.3%) refused participation with concerns over LP being the most commonly reported reason. Relatively more African Americans than Caucasians reported concerns over LP as the main reason for non-participation (46% vs. 25%, p = 0.03), but more African Americans also did not provide a specific reason for non-participation. Among those who completed study participation (including the LP), African Americans and Caucasians were similar in pre-LP perceptions and reluctance, as well as post-LP rates of discomfort or complication. Perceiving LP as a frightening invasive procedure, not race, is associated with increased likelihood of post-LP discomfort or complication (RR 6.2, 95% confidence interval 1.1–37.0). Our results indicate that LP is a well perceived procedure in a cohort of African American and Caucasian research participants, and is associated with few serious complications. The pre-procedure perception that the LP is a frightening invasive procedure significantly increases the risk of self-reported discomfort of complications, and African Americans may be more likely to turn down study participation because of the LP. Future studies will need to address factors associated with negative LP perceptions to further assure participants and reduce complication rates.