Transcription factor Nr4a1 couples sympathetic and inflammatory cues in CNS-recruited macrophages to limit neuroinflammation.

The molecular mechanisms that link the sympathetic stress response and inflammation remain obscure. Here we found that the transcription factor Nr4a1 regulated the production of norepinephrine (NE) in macrophages and thereby limited experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Lack of Nr4a1 in myeloid cells led to enhanced NE production, accelerated infiltration of leukocytes into the central nervous system (CNS) and disease exacerbation in vivo. In contrast, myeloid-specific deletion of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis, protected mice against EAE. Furthermore, we found that Nr4a1 repressed autocrine NE production in macrophages by recruiting the corepressor CoREST to the Th promoter. Our data reveal a new role for macrophages in neuroinflammation and identify Nr4a1 as a key regulator of catecholamine production by macrophages.

Differential effects of anti-CD20 therapy on CD4 and CD8 T cells and implication of CD20-expressing CD8 T cells in MS disease activity.

A small proportion of multiple sclerosis (MS) patients develop new disease activity soon after starting anti-CD20 therapy. This activity does not recur with further dosing, possibly reflecting deeper depletion of CD20-expressing cells with repeat infusions. We assessed cellular immune profiles and their association with transient disease activity following anti-CD20 initiation as a window into relapsing disease biology. Peripheral blood mononuclear cells from independent discovery and validation cohorts of MS patients initiating ocrelizumab were assessed for phenotypic and functional profiles using multiparametric flow cytometry. Pretreatment CD20-expressing T cells, especially CD20dimCD8+ T cells with a highly inflammatory and central nervous system (CNS)-homing phenotype, were significantly inversely correlated with pretreatment MRI gadolinium-lesion counts, and also predictive of early disease activity observed after anti-CD20 initiation. Direct removal of pretreatment proinflammatory CD20dimCD8+ T cells had a greater contribution to treatment-associated changes in the CD8+ T cell pool than was the case for CD4+ T cells. Early disease activity following anti-CD20 initiation was not associated with reconstituting CD20dimCD8+ T cells, which were less proinflammatory compared with pretreatment. Similarly, this disease activity did not correlate with early reconstituting B cells, which were predominantly transitional CD19+CD24highCD38high with a more anti-inflammatory profile. We provide insights into the mode-of-action of anti-CD20 and highlight a potential role for CD20dimCD8+ T cells in MS relapse biology; their strong inverse correlation with both pretreatment and early posttreatment disease activity suggests that CD20-expressing CD8+ T cells leaving the circulation (possibly to the CNS) play a particularly early role in the immune cascades involved in relapse development.

Improvement of Refractory Systemic Juvenile Idiopathic Arthritis-Associated Lung Disease with Single-Agent Blockade of IL-1ß and IL-18.

Systemic juvenile idiopathic arthritis associated with interstitial lung disease (SJIA-LD) represents a highly morbid subset of SJIA for which effective therapies are lacking. We report the case of a patient with refractory SJIA-LD who underwent treatment with MAS-825, an investigational bispecific monoclonal antibody targeting IL-1ß and IL-18. MAS-825 treatment was associated with a marked reduction in total IL-18 and free IL-18 in both serum and bronchoalveolar lavage fluid (BAL). Baseline oxygen saturation, exercise tolerance, and quality of life metrics improved after treatment with MAS-825, while pulmonary function testing remained stable. Following treatment, the BAL showed no evidence of pulmonary alveolar proteinosis and inflammatory infiltrates were markedly reduced, reflected by decreased numbers of CD4 T-cells, CD8 T-cells, and macrophages. The patient was able to wean entirely off systemic corticosteroids and other biologics after 10 months of treatment with MAS-825 and experienced no side effects of the drug. This case demonstrates improvement in pulmonary symptoms, lung inflammation, and burden of immunomodulatory therapy after treatment with MAS-825 and suggests that simultaneous targeting of both IL-1ß and IL-18 may be a safe and effective treatment strategy in SJIA-LD.

Utilizing trapped charge at bilayer 2D MoS2/SiO2interface for memory applications.

In this work we use conductive atomic force microscopy (cAFM) to study the charge injection process from a nanoscale tip to a single isolated bilayer 2D MoS2flake. The MoS2is exfoliated and bonded to ultra-thin SiO2/Si substrate. Local current-voltage (IV) measurements conducted by cAFM provides insight in charge trapping/de-trapping mechanisms at the MoS2/SiO2interface. The MoS2nano-flake provides an adjustable potential barrier for embedded trap sites where the charge is injected from AFM tip is confined at the interface. A window of (ΔV∼ 1.8 V) is obtain at a reading current of 2 nA between two consecutiveIVsweeps. This is a sufficient window to differentiate between the two states indicating memory behavior. Furthermore, the physics behind the charge entrapment and its contribution to the tunneling mechanisms is discussed.

Improved figures of merit of nano-Schottky diode by embedding and characterizing individual gold nanoparticles on n-Si substrates.

Improving Schottky diode characteristics in semiconducting devices is essential for better functionality in electronic and optoelectronic devices at nanoscale. In this paper, we investigate the electric transport characteristics of a gold (Au)-tip/n-Si-based nano-Schottky diode by using a conductive-mode atomic force microscope (CAFM). First, 10 nm average diameter Au nanoparticles (NPs) are monodispersed on the highly cleaned n-type Si substrate using an optimized spin-coating technique. The controlled and well dispersed NPs are confirmed by using the AC imaging mode of the AFM. The electrical characteristics are established by using an Au-coated AFM tip, by either soft engaging at the surface of the n-Si substrate or at the top of an individual Au NP. Landing of the AFM tip on the NP or n-Si substrate is validated by the force curves of the AFM. From the localized CAFM electrical characteristics, we observed the improvement in the figures of merit (FOM) that characterize the rectification performance including the (1-V) asymmetry (f ASYM), and the turn-on voltage due to placing the Au NP between the AFM tip and n-Si substrate. These improved FOM of the nanoscale diodes are explained based on the increase in the tunneling current at the nanoscale Au-NP/n-Si interface. Moreover, the nanoscale control of interface structure is extremely important to improve the characteristics of nano-Schottky diodes.

Abnormal effector and regulatory T cell subsets in paediatric-onset multiple sclerosis.

Elucidation of distinct T-cell subsets involved in multiple sclerosis immune-pathophysiology continues to be of considerable interest since an ultimate goal is to more selectively target the aberrant immune response operating in individual patients. While abnormalities of both effector (Teff) and regulatory (Treg) T cells have been reported in patients with multiple sclerosis, prior studies have mostly assessed average abnormalities in either limb of the immune response, rather than both at the same time, which limits the ability to evaluate the balance between effectors and regulators operating in the same patient. Assessing both phenotypic and functional responses of Teffs and Tregs has also proven important. In studies of adults with multiple sclerosis, in whom biological disease onset likely started many years prior to the immune assessments, an added challenge for any reported abnormality is whether the abnormality indeed contributes to the disease (and hence of interest to target therapeutically) or merely develops consequent to inflammatory injury (in which case efforts to develop targeted therapies are unlikely to be beneficial). Paediatric-onset multiple sclerosis, though rare, offers a unique window into early disease mechanisms. Here, we carried out a comprehensive integrated study, simultaneously assessing phenotype and functional responses of both effector and regulatory T cells in the same children with multiple sclerosis, monophasic inflammatory CNS disorders, and healthy controls, recruited as part of the multicentre prospective Canadian Pediatric Demyelinating Disease Study (CPDDS). Stringent standard operating procedures were developed and uniformly applied to procure, process and subsequently analyse peripheral blood cells using rigorously applied multi-parametric flow cytometry panels and miniaturized functional assays validated for use with cryopreserved cells. We found abnormally increased frequencies and exaggerated pro-inflammatory responses of CD8+CD161highTCR-Vα7.2+ MAIT T cells and CD4+CCR2+CCR5+ Teffs in paediatric-onset multiple sclerosis, compared to both control groups. CD4+CD25hiCD127lowFOXP3+ Tregs of children with multiple sclerosis exhibited deficient suppressive capacity, including diminished capacity to suppress disease-implicated Teffs. In turn, the implicated Teffs of multiple sclerosis patients were relatively resistant to suppression by normal Tregs. An abnormal Teff/Treg ratio at the individual child level best distinguished multiple sclerosis children from controls. We implicate abnormalities in both frequencies and functional responses of distinct pro-inflammatory CD4 and CD8 T cell subsets, as well as Treg function, in paediatric-onset multiple sclerosis, and suggest that mechanisms contributing to early multiple sclerosis development differ across individuals, reflecting an excess abnormality in either Teff or Treg limbs of the T cell response, or a combination of lesser abnormalities in both limbs.

Antibody-Independent Function of Human B Cells Contributes to Antifungal T Cell Responses.

Fungal infections (e.g., Candida albicans) can manifest as serious medical illnesses, especially in the elderly and immune-compromised hosts. T cells are important for Candida control. Whether and how B cells are involved in antifungal immunity has been less clear. Although patients with agammaglobulinemia exhibit normal antifungal immunity, increased fungal infections are reported following B cell-depleting therapy, together pointing to Ab-independent roles of B cells in controlling such infections. To test how human B cells may contribute to fungal-associated human T cell responses, we developed a novel Ag-specific human T cell/B cell in vitro coculture system and found that human B cells could induce C. albicans-associated, MHC class II-restricted responses of naive T cells. Activated B cells significantly enhanced C. albicans-mediated Th1 and Th17 T cell responses, which were both strongly induced by CD80/CD86 costimulation. IL-6+GM-CSF+ B cells were the major responding B cell subpopulation to C. albicans and provided efficient costimulatory signals to the T cells. In vivo B cell depletion in humans resulted in reduced C. albicans-associated T responses. Of note, the decreased Th17, but not Th1, responses could be reversed by soluble factors from B cells prior to depletion, in an IL-6-dependent manner. Taken together, our results implicate an Ab-independent cytokine-defined B cell role in human antifungal T cell responses. These findings may be particularly relevant given the prospects of chronic B cell depletion therapy use in lymphoma and autoimmune disease, as patients age and are exposed to serial combination therapies.

Dimethyl Fumarate Treatment Mediates an Anti-Inflammatory Shift in B Cell Subsets of Patients with Multiple Sclerosis.

The therapeutic mode of action of dimethyl fumarate (DMF), approved for treating patients with relapsing-remitting multiple sclerosis, is not fully understood. Recently, we and others demonstrated that Ab-independent functions of distinct B cell subsets are important in mediating multiple sclerosis (MS) relapsing disease activity. Our objective was to test whether and how DMF influences both the phenotype and functional responses of disease-implicated B cell subsets in patients with MS. High-quality PBMC were obtained from relapsing-remitting MS patients prior to and serially after initiation of DMF treatment. Multiparametric flow cytometry was used to monitor the phenotype and functional response-profiles of distinct B cell subsets. Total B cell counts decreased following DMF treatment, largely reflecting losses of circulating mature/differentiated (but not of immature transitional) B cells. Within the mature B cell pool, DMF had a greater impact on memory than naive B cells. In keeping with these in vivo effects, DMF treatment in vitro remarkably diminished mature (but not transitional B cell) survival, mediated by inducing apoptotic cell death. Although DMF treatment (both in vivo and in vitro) minimally impacted B cell IL-10 expression, it strongly reduced B cell expression of GM-CSF, IL-6, and TNF-α, resulting in a significant anti-inflammatory shift of B cell response profiles. The DMF-mediated decrease in B cell proinflammatory cytokine responses was further associated with reduced phosphorylation of STAT5/6 and NF-κB in surviving B cells. Together, these data implicate novel mechanisms by which DMF may modulate MS disease activity through shifting the balance between pro- and anti-inflammatory B cell responses.

Treatment response to dimethyl fumarate is characterized by disproportionate CD8+ T cell reduction in MS.

BACKGROUND: The effect of dimethyl fumarate (DMF) on circulating lymphocyte subsets and their contribution as predictors of clinical efficacy have not yet been investigated in multiple sclerosis (MS). OBJECTIVE: To evaluate lymphocytes and lymphocyte subsets (analyzed 6 months after DMF start) in MS patients with and without disease activity after 1 year of treatment in a retrospective study. METHODS: Peripheral blood lymphocyte subsets were analyzed by flow cytometry. Untreated MS patients ( n = 40) were compared to those 6 months after onset of DMF treatment ( n = 51). Clinical and magnetic resonance imaging (MRI) disease activity of DMF-treated patients were assessed in the first year under treatment. RESULTS: Stable patients showed significantly lower lymphocytes, CD4+ and CD8+ T cells as well as CD19+ B cells compared to active patients under DMF treatment. Furthermore, an increased CD4/CD8 ratio ( p < 0.025) in stable patients indicated a disproportionate reduction of CD8+ T cells relative to CD4+ T cells. Reduced lymphocytes, CD8+ T cells, and CD19+ B cells 6 months after DMF start allowed prediction of the treatment response in the first year. CONCLUSION: DMF treatment response is reflected by lower circulating lymphocytes and specific lymphocyte subsets. Changes in the cellular immune profiles under DMF treatment are clinically relevant and might serve as a surrogate marker of treatment response.

MerTK Is a Functional Regulator of Myelin Phagocytosis by Human Myeloid Cells.

Multifocal inflammatory lesions featuring destruction of lipid-rich myelin are pathologic hallmarks of multiple sclerosis. Lesion activity is assessed by the extent and composition of myelin uptake by myeloid cells present in such lesions. In the inflamed CNS, myeloid cells are comprised of brain-resident microglia, an endogenous cell population, and monocyte-derived macrophages, which infiltrate from the systemic compartment. Using microglia isolated from the adult human brain, we demonstrate that myelin phagocytosis is dependent on the polarization state of the cells. Myelin ingestion is significantly enhanced in cells exposed to TGF-ß compared with resting basal conditions and markedly reduced in classically activated polarized cells. Transcriptional analysis indicated that TGF-ß-treated microglia closely resembled M0 cells. The tyrosine kinase phagocytic receptor MerTK was one of the most upregulated among a select number of differentially expressed genes in TGF-ß-treated microglia. In contrast, MerTK and its known ligands, growth arrest-specific 6 and Protein S, were downregulated in classically activated cells. MerTK expression and myelin phagocytosis were higher in CNS-derived microglia than observed in monocyte-derived macrophages, both basally and under all tested polarization conditions. Specific MerTK inhibitors reduced myelin phagocytosis and the resultant anti-inflammatory biased cytokine responses for both cell types. Defining and modulating the mechanisms that regulate myelin phagocytosis has the potential to impact lesion and disease evolution in multiple sclerosis. Relevant effects would include enhancing myelin clearance, increasing anti-inflammatory molecule production by myeloid cells, and thereby permitting subsequent tissue repair.

Reconstitution of the peripheral immune repertoire following withdrawal of fingolimod.

BACKGROUND: Following fingolimod cessation, immune reconstitution or lack thereof may have consequences for disease rebound or safety of commencing alternative therapies. OBJECTIVE: To examine the degree and profile of peripheral blood lymphocyte reconstitution following fingolimod withdrawal. METHODS: Total lymphocyte counts (TLC) and CD4+/CD8+ T-cell counts were measured in 18 multiple sclerosis (MS) patients pre-treatment, on fingolimod, and up to 8-9 months post-cessation. T-cell subsets were analyzed using flow cytometry. RESULTS: At 2-week post-fingolimod cessation, TLC reconstitution was variable and not correlated with age, treatment duration, pre-, or on-treatment TLC. Despite normalization of TLC and CD4+:CD8+ ratios over months, naive subsets remained lower and effector memory subsets higher in frequency compared with pre-treatment. Drug-induced increases in ratios of regulatory to pathogenic Th17-containing central memory populations appeared to rapidly return to baseline. CONCLUSION: Early peripheral lymphocyte reconstitution after fingolimod withdrawal remains partial and heterogeneous. Relative frequencies of circulating naive and memory T-cell subsets may not recover for many months, even when clinical laboratory tests have normalized. Analyzing specific components of the peripheral immune repertoire helps define the overall immune status of patients. To be determined is whether assessment of such immune measures will have implications for the timing and safety of commencing alternative therapies.

Role of IL-17-producing lymphocytes in severity of multiple sclerosis upon natalizumab treatment.

OBJECTIVE: Natalizumab is known to prevent T-helper cells entering the central nervous system (CNS). We hypothesize that more pathogenic T-helper cells are present outside the CNS and a possible relationship to disease severity. METHODS: Characterization and enrichment of human CD4+IL-17+ cells were performed ex vivo using peripheral blood mononuclear cells from natalizumab-treated relapsing-remitting multiple sclerosis (RRMS) patients ( n = 33), untreated RRMS patients ( n = 13), and healthy controls ( n = 33). Magnetic resonance imaging (MRI) scans were performed routinely for patients. RESULTS: Lymphocytes were elevated in peripheral blood of natalizumab-treated patients compared to untreated patients and healthy controls. Whereas group comparison for CD4+IL-17+ numbers also differed, CD4+IFN-γ+ and CD4+IL-22+ counts were not increased. CD4+IL-17+ cells not only expressed but also secreted IL-17. In natalizumab-treated patients, IL-17+ cell frequency was found to correlate with T1-hypointense lesions, but was not an indicator for rebound activity after treatment discontinuation, except in one patient who experienced a fulminant rebound, and interestingly, in whom the highest IL-17+ cell levels were observed. CONCLUSION: Increased lymphocytes and CD4+IL-17+ cells in the blood of RRMS patients receiving natalizumab corroborate the drug's mechanism of action, that is, blocking transmigration to CNS. Correlation between IL-17-expressing lymphocytes and T1-hypointense lesions underlines the important role of these cells in the disease pathology.

A carbonyl-decorated two-dimensional polymer as a charge-trapping layer for non-volatile memory storage devices with a high endurance and wide memory window.

The charge-trapping mechanism in conjugated polymers is a performance obstacle in many optoelectronic devices harnessed for non-volatile memory applications. Herein, a carbonyl-decorated organic 2D-polymer (TpDb)-based charge-trapping memory device has been developed with a wide memory window (3.2 V) with low programming and erasing voltages of +3/-2 and -3/+2. The TpDb was synthesized by a potentially scalable solid-state aldol condensation reaction. The inherent structural defects and the semi-conjugated nature of the enone network in TpDb offer effective charge-trapping through the localization of charges in specific functional groups (CO). The interlayer hydrogen bonding enhances the packing density of the 2D-polymer layers thereby improving the memory storage properties of the material. Furthermore, the TpDb exhibits excellent features for non-volatile memory applications including over 10 000 cycles of write/read endurance and a prolonged retention performance of 104 seconds at high temperatures (100 °C).

Oxidative phosphorylation regulates B cell effector cytokines and promotes inflammation in multiple sclerosis.

Dysregulated B cell cytokine production contributes to pathogenesis of immune-mediated diseases including multiple sclerosis (MS); however, the underlying mechanisms are poorly understood. In this study we investigated how cytokine secretion by pro-inflammatory (GM-CSF-expressing) and anti-inflammatory (IL-10-expressing) B cells is regulated. Pro-inflammatory human B cells required increased oxidative phosphorylation (OXPHOS) compared with anti-inflammatory B cells. OXPHOS reciprocally modulated pro- and anti-inflammatory B cell cytokines through regulation of adenosine triphosphate (ATP) signaling. Partial inhibition of OXPHOS or ATP-signaling including with BTK inhibition resulted in an anti-inflammatory B cell cytokine shift, reversed the B cell cytokine imbalance in patients with MS, and ameliorated neuroinflammation in a myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalitis mouse model. Our study identifies how pro- and anti-inflammatory cytokines are metabolically regulated in B cells and identifies ATP and its metabolites as a "fourth signal" that shapes B cell responses and is a potential target for restoring the B cell cytokine balance in autoimmune diseases.

Artificial visual perception neural system using a solution-processable MoS2-based in-memory light sensor.

Optoelectronic devices are advantageous in in-memory light sensing for visual information processing, recognition, and storage in an energy-efficient manner. Recently, in-memory light sensors have been proposed to improve the energy, area, and time efficiencies of neuromorphic computing systems. This study is primarily focused on the development of a single sensing-storage-processing node based on a two-terminal solution-processable MoS2 metal-oxide-semiconductor (MOS) charge-trapping memory structure-the basic structure for charge-coupled devices (CCD)-and showing its suitability for in-memory light sensing and artificial visual perception. The memory window of the device increased from 2.8 V to more than 6 V when the device was irradiated with optical lights of different wavelengths during the program operation. Furthermore, the charge retention capability of the device at a high temperature (100 °C) was enhanced from 36 to 64% when exposed to a light wavelength of 400 nm. The larger shift in the threshold voltage with an increasing operating voltage confirmed that more charges were trapped at the Al2O3/MoS2 interface and in the MoS2 layer. A small convolutional neural network was proposed to measure the optical sensing and electrical programming abilities of the device. The array simulation received optical images transmitted using a blue light wavelength and performed inference computation to process and recognize the images with 91% accuracy. This study is a significant step toward the development of optoelectronic MOS memory devices for neuromorphic visual perception, adaptive parallel processing networks for in-memory light sensing, and smart CCD cameras with artificial visual perception capabilities.

A Rational Design of Isoindigo-Based Conjugated Microporous n-Type Semiconductors for High Electron Mobility and Conductivity.

The development of n-type organic semiconductors has evolved significantly slower in comparison to that of p-type organic semiconductors mainly due to the lack of electron-deficient building blocks with stability and processability. However, to realize a variety of organic optoelectronic devices, high-performance n-type polymer semiconductors are essential. Herein, conjugated microporous polymers (CMPs) comprising isoindigo acceptor units linked to benzene or pyrene donor units (BI and PI) showing n-type semiconducting behavior are reported. In addition, considering the challenges of deposition of a continuous and homogeneous thin film of CMPs for accurate Hall measurements, a plasma-assisted fabrication technique is developed to yield uniform thin films. The fully conjugated 2D networks in PI- and BI-CMP films display high electron mobility of 6.6 and 3.5 cm2 V-1 s-1 , respectively. The higher carrier concentration in PI results in high conductivity (5.3 mS cm-1 ). Both experimental and computational studies are adequately combined to investigate structure-property relations for this intriguing class of materials in the context of organic electronics.

Nano-scale charge trapping memory based on two-dimensional conjugated microporous polymer.

There is a growing interest in new semiconductor nanostructures for future high-density high-performance flexible electronic devices. Two-dimensional conjugated microporous polymers (2D-CMPs) are promising candidates because of their inherent optoelectronic properties. Here, we are reporting a novel donor-acceptor type 2D-CMP based on Pyrene and Isoindigo (PI) for a potential nano-scale charge-trapping memory application. We exfoliated the PI polymer into ~ 2.5 nm thick nanoparticles (NPs) and fabricated a Metal-Insulator-Semiconductor (MIS) device with PI-NPs embedded in the insulator. Conductive AFM (cAFM) is used to examine the confinement mechanism as well as the local charge injection process, where ultrathin high-κ alumina supplied the energy barrier for confining the charge carrier transport. We have achieved a reproducible on-and-off state and a wide memory window (ΔV) of 1.5 V at a relatively small reading current. The device displays a low operation voltage (V < 1 V), with good retention (104 s), and endurance (103 cycles). Furthermore, a theoretical analysis is developed to affirm the measured charge carriers' transport and entrapment mechanisms through and within the fabricated MIS structures. The PI-NPs act as a nanoscale floating gate in the MIS-based memory with deep trapping sites for the charged carriers. Moreover, our results demonstrate that the synthesized 2D-CMP can be promising for future low-power high-density memory applications.

Abnormal B-Cell and Tfh-Cell Profiles in Patients With Parkinson Disease: A Cross-sectional Study.

BACKGROUND AND OBJECTIVES: There has been growing interest in potential roles of the immune system in the pathogenesis of Parkinson disease (PD). The aim of the current study was to comprehensively characterize phenotypic and functional profiles of circulating immune cells in patients with PD vs controls. METHODS: Peripheral blood was collected from patients with PD and age- and sex-matched neurologically normal controls (NCs) in 2 independent cohorts (discovery and validation). Comprehensive multicolor flow cytometry was performed on whole blood leukocytes and peripheral blood mononuclear cells to characterize different immune subsets and their ex vivo responses. RESULTS: The discovery cohort included 17 NCs and 12 participants with PD, and the validation cohort included 18 NCs and 18 participants with PD. Among major immune cell types, B cells appeared to be preferentially affected in PD. Proliferating B cell counts were decreased in patients with PD compared with controls. Proportions of B-cell subsets with regulatory capacity such as transitional B cells were preferentially reduced in the patients with PD, whereas proportions of proinflammatory cytokine-producing B cells increased, resulting in a proinflammatory shift of their B-cell functional cytokine responses. Unsupervised principal component analysis revealed increased expression of TNFα and GM-CSF by both B cells and T cells of patients with PD. In addition, levels of follicular T cells, an important B-cell helper T-cell population, decreased in the patients with PD, correlating with their B-cell abnormality. DISCUSSION: Our findings define a novel signature of peripheral immune cells and implicate aberrant Tfh:B-cell interactions in patients with PD.

Immune aging in multiple sclerosis is characterized by abnormal CD4 T cell activation and increased frequencies of cytotoxic CD4 T cells with advancing age.

BACKGROUND: Immunosenescence (ISC) describes age-related changes in immune-system composition and function. Multiple sclerosis (MS) is a lifelong inflammatory condition involving effector and regulatory T-cell imbalance, yet little is known about T-cell ISC in MS. We examined age-associated changes in circulating T cells in MS compared to normal controls (NC). METHODS: Forty untreated MS (Mean Age 43·3, Range 18-72) and 49 NC (Mean Age 48·6, Range 20-84) without inflammatory conditions were included in cross-sectional design. T-cell subsets were phenotypically and functionally characterized using validated multiparametric flow cytometry. Their aging trajectories, and differences between MS and NC, were determined using linear mixed-effects models. FINDINGS: MS patients demonstrated early and persistent redistribution of naïve and memory CD4 T-cell compartments. While most CD4 and CD8 T-cell aging trajectories were similar between groups, MS patients exhibited abnormal age-associated increases of activated (HLA-DR+CD38+; (P = 0·013) and cytotoxic CD4 T cells, particularly in patients >60 (EOMES: P < 0·001). Aging MS patients also failed to upregulate CTLA-4 expression on both CD4 (P = 0·014) and CD8 (P = 0·009) T cells, coupled with abnormal age-associated increases in frequencies of B cells expressing costimulatory molecules. INTERPRETATION: While many aspects of T-cell aging in MS are conserved, the older MS patients harbour abnormally increased frequencies of CD4 T cells with activated and cytotoxic effector profiles. Age-related decreased expression of T-cell co-inhibitory receptor CTLA-4, and increased B-cell costimulatory molecule expression, may provide a mechanism that drives aberrant activation of effector CD4 T cells that have been implicated in progressive disease. FUNDING: Stated in Acknowledgements section of manuscript.