Intralymphatic GAD-alum Injection Modulates B Cell Response and Induces Follicular Helper T Cells and PD-1+ CD8+ T Cells in Patients With Recent-Onset Type 1 Diabetes

Antigen-specific immunotherapy is an appealing strategy to preserve beta-cell function in type 1 diabetes, although the approach has yet to meet its therapeutic endpoint. Direct administration of autoantigen into lymph nodes has emerged as an alternative administration route that can improve the efficacy of the treatment. In the first open-label clinical trial in humans, injection of aluminum-formulated glutamic acid decarboxylase (GAD-alum) into an inguinal lymph node led to the promising preservation of C-peptide in patients with recent-onset type 1 diabetes. The treatment induced a distinct immunomodulatory effect, but the response at the cell level has not been fully characterized. Here we used mass cytometry to profile the immune landscape in peripheral blood mononuclear cells from 12 participants of the study before and after 15 months of treatment. The immunomodulatory effect of the therapy included reduction of naïve and unswitched memory B cells, increase in follicular helper T cells and expansion of PD-1+ CD69+ cells in both CD8+ and double negative T cells. In vitro stimulation with GAD65 only affected effector CD8+ T cells in samples collected before the treatment. However, the recall response to antigen after 15 months included induction of CXCR3+ and CD11c+Tbet+ B cells, PD-1+ follicular helper T cells and exhausted-like CD8+ T cells. This study provides a deeper insight into the immunological changes associated with GAD-alum administration directly into the lymph nodes.

Neuroimmunological investigations of cerebrospinal fluid in patients with recent onset depression – a study protocol

Background A proinflammatory response has been suggested to be involved in the pathophysiology of depression in a subgroup of patients. However, comprehensive largescale studies on neuroimmunological investigations of the cerebrospinal fluid (CSF) are lacking and no largescale longitudinal CSF studies comparing patients with depression to healthy controls currently exist. Methods A longitudinal case-control study including at least 100 patients with first time depression (ICD-10: F32) within the past year with ongoing symptoms and at least 100 sex and age matched healthy controls with collection of CSF, blood, and fecal samples. All individuals will be evaluated by neurological examination including neurological soft signs, interviewed for psychopathology assessment and have symptomatology evaluated by relevant rating scales. Level of functioning and quality of life will be evaluated by a panel of interview questions and rating scales, and cognitive function assessed by a relevant test battery. In addition, a large number of potential confounders will be registered (BMI, smoking status, current medication etc.). Primary outcomes: CSF white cell count, CSF/serum albumin ratio, CSF total protein levels, IgG index, CSF levels of IL-6 and IL-8, and the prevalence of any CNS-reactive autoantibody in CSF and/or blood. Secondary outcomes: exploratory analyses of a wide range of neuroimmunological markers and specific autoantibodies. Power calculations are computed for all primary outcomes based on previous CSF studies including patients with depression and healthy controls. Discussion This study will represent the hitherto largest investigation of CSF in patients with recent onset depression compared to healthy controls. We expect to elucidate neuroimmunological alterations in individuals with depression and characterize an immunological profile paving the way for the development of effective treatments based on biomarkers. Trial registration The study is approved by The Regional Committee on Health Research Ethics (Capital Region, j.no: H-16030985) and The Danish Data Protection Agency (j.no: RHP-2016-020, I-Suite no.: 04945).

Prevalence of Inflammatory Pathways Over Immuno-Tolerance in Peripheral Blood Mononuclear Cells of Recent-Onset Type 1 Diabetes

BackgroundChanges in innate and adaptive immunity occurring in/around pancreatic islets had been observed in peripheral blood mononuclear cells (PBMC) of Caucasian T1D patients by some, but not all researchers. The aim of our study was to investigate whether gene expression patterns of PBMC of the highly admixed Brazilian population could add knowledge about T1D pathogenic mechanisms.MethodsWe assessed global gene expression in PBMC from two groups matched for age, sex and BMI: 20 patients with recent-onset T1D (≤ 6 months from diagnosis, in a time when the autoimmune process is still highly active), testing positive for one or more islet autoantibodies and 20 islet autoantibody-negative healthy controls.ResultsWe identified 474 differentially expressed genes between groups. The most expressed genes in T1D group favored host defense, inflammatory and anti-bacterial/antiviral effects (LFT, DEFA4, DEFA1, CTSG, KCNMA1) and cell cycle progression. Several of the downregulated genes in T1D target cellular repair, control of inflammation and immune tolerance. They were related to T helper 2 pathway, induction of FOXP3 expression (AREG) and immune tolerance (SMAD6). SMAD6 expression correlated negatively with islet ZnT8 antibody. The expression of PDE12, that offers resistance to viral pathogens was decreased and negatively related to ZnT8A and GADA levels. The increased expression of long non coding RNAs MALAT1 and NEAT1, related to inflammatory mediators, autoimmune diseases and innate immune response against viral infections reinforced these dataConclusionsOur analysis suggested the activation of cell development, anti-infectious and inflammatory pathways, indicating immune activation, whereas immune-regulatory pathways were downregulated in PBMC from recent-onset T1D patients with a differential genetic profile.

Therapeutic Challenge in a Case of Recent Onset Refractory Cluster Seizures

A dilemma exists in context to the timing of surgery in a case presenting with explosive onset seizures secondary to a focal cortical dysplasia (FCD). This case report highlights the challenges faced in the management of a 4-year-old child with recent onset cluster seizures refractory to anti-epileptic drugs. A 4-year-old girl presented with an acute onset of cluster seizures (up to 32 in a day), semiologically characterized by tonic upper limb extension and laughter lasting for few seconds with no response to multiple anti-epileptic drugs. The clinical, electrographic, neuroimaging and interictal positron emission tomography data were concordant and consistent with a left middle frontal gyrus dysplasia which was successfully resected under electrocorticographic guidance. Patient is seizure free at 2 months of follow up. (Engel Class 1). Surgical resection is feasible and potentially more effective in the early phase of clinical presentation of FCD.

Functional Network Connectivity Imprint In Febrile Seizures

Complex febrile seizures (CFS), a subset of paediatric febrile seizures (FS), have been studied for their prognosis, epileptogenic potential and neurocognitive outcome. We evaluated their functional connectivity differences with simple febrile seizures (SFS) in children with recent-onset FS. Resting-state fMRI (rsfMRI) datasets of 24 children with recently diagnosed FS (SFS n=11; CFS n=13) were analysed. Functional connectivity (FC) was estimated using time series correlation of seed region to whole brain voxels and network topology was assessed using graph theory measures. Regional connectivity differences were correlated with clinical characteristics (FDR corrected p < 0.05). CFS patients demonstrated increased FC of the bilateral middle temporal pole (MTP), and bilateral thalami when compared to SFS. Network topology study revealed increased clustering coefficient and decreased participation coefficient in basal ganglia and thalamus suggesting an inefficient-unbalanced network topology in patients with CFS. The number of seizure recurrences negatively correlated with the integration of Left Thalamus ( r= -0.58 ) and FC measures of Left MTP to 'Right Supplementary Motor and left Precentral' connectivity (r=-0.53). The FC of Right MTP to Left Amygdala, Putamen, Parahippocampal, and Orbital Frontal Cortex ( r=0.61 ) and FC of Left Thalamus to left Putamen, Pallidum, Caudate, Thalamus Hippocampus and Insula (r 0.55) showed a positive correlation to the duration of the longest seizure. The findings of the current study report altered connectivity in children with CFS proportional to the seizure recurrence and duration. Regardless of the causal/consequential nature, such observations demonstrate the imprint of these disease-defining variables of febrile seizures on the developing brain.

Randomized Controlled Trial of Early Outpatient COVID-19 Treatment with High-Titer Convalescent Plasma

BACKGROUND: The efficacy of polyclonal high titer convalescent plasma to prevent serious complications of COVID-19 in outpatients with recent onset of illness is uncertain. METHODS: This multicenter, double-blind randomized controlled trial compared the efficacy and safety of SARS-CoV-2 high titer convalescent plasma to placebo control plasma in symptomatic adults >18 years positive for SARS-CoV-2 regardless of risk factors for disease progression or vaccine status. Participants with symptom onset within 8 days were enrolled, then transfused within the subsequent day. The measured primary outcome was COVID-19-related hospitalization within 28 days of plasma transfusion. The enrollment period was June 3, 2020 to October 1, 2021. RESULTS: A total of 1225 participants were randomized and 1181 transfused. In the pre-specified modified intention-to-treat analysis that excluded those not transfused, the primary endpoint occurred in 37 of 589 (6.3%) who received placebo control plasma and in 17 of 592 (2.9%) participants who received convalescent plasma (relative risk, 0.46; one-sided 95% upper bound confidence interval 0.733; P=0.004) corresponding to a 54% risk reduction. Examination with a model adjusting for covariates related to the outcome did not change the conclusions. CONCLUSION: Early administration of high titer SARS-CoV-2 convalescent plasma reduced outpatient hospitalizations by more than 50%. High titer convalescent plasma is an effective early outpatient COVID-19 treatment with the advantages of low cost, wide availability, and rapid resilience to variant emergence from viral genetic drift in the face of a changing pandemic.

The Need for SPACE to Plan the Future for Spondyloarthritis

"Lifestyle Factors and Disease Activity Over Time in Early Axial Spondyloarthritis: The SPondyloArthritis Caught Early (SPACE) Cohort" by Exarchou et al aimed at looking at the importance of baseline lifestyle factors of BMI, smoking, and alcohol consumption (AC) on disease activity in recent-onset axial spondyloarthritis (axSpA).1 Does this study add to our knowledge of the natural history of axSpA?

A new animal model signifying a decisive bridge between innate immunity and the pathognomonic morphological characteristics of Type 1 Diabetes

Available animal models for Type 1 Diabetes (T1D) show limited similarities with the human disease and have no predictive value in screening for effective intervention therapies. Heat-inactivated bacteria instilled in the ductal compartment of the pancreas in healthy rats rapidly cause periductal inflammation and accumulation of mainly granulocytes and monocytes in the exocrine pancreas and in the peri-islet area mimicking the acute pancreatic inflammation in subjects with recent onset T1D. After three weeks, the triggered exocrine inflammation had vanished and pancreases showed normal morphology. However, a distinct accumulation of both CD4+ and CD8+ T cells within and adjacent to affected islets was found in one third of the rats, mimicking the pathognomonic insulitis in T1D. As in human T1D, the insulitis affected a fraction of all islets and was observed only in certain lobes of the pancreases. The presented animal model for T1D will allow detailed mechanistic studies to unravel a previously unknown interplay between bacteria-activated innate immunity and an acquired cellular immunity forming the immunopathological events described in humans at different stages of T1D.Summary StatementThe results presented signify a previously unknown decisive bridge between innate immunity and formation of the pathognomonic immunopathological events described in subjects with recent onset T1D.